bluuebunny/crossref_metadata_2025_split huggingface dataset:
A retrospective study evaluating clinical and molecular predictors of duration of response (DoR) to immune checkpoint inhibitors (ICI) in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Ibrahim Yahya , Sankar Keerthana , Kim Seongho , Haddad Amy , Mamdani Hirva 
Published: May 2020

e21581 Background: ICI with/without chemotherapy has become the standard of care for the treatment of advanced NSCLC. Little is known about the clinical and molecular predictors of DoR to these agents. We previously reported clinical predictors of DoR to ICI in NSCLC patients (pts). Here we report the correlation of molecular alterations with DoR and clinical/molecular characteristics of super responders (DoR ≥ 2yr) to ICI. Methods: A retrospective chart review of pts with advanced NSCLC treated with ICI based therapy between 2015-2018 at Karmanos Cancer Institute was conducted. Clinical, tumor, and molecular characteristics data were collected. DoR was grouped into: < / = 6 weeks, > 6weeks-6months, > 6mo-1yr, > 1yr, and super responders. Results: Of 147 pts, 68% had adenocarcinoma, 61% received prior radiation, 21% had brain metastasis (mets), 26% developed irAEs, 33% were on statin, 27% were on aspirin, 83% were current or former smokers, 55% had right sided primary tumor, ICI was 1st line treatment (tx) in 20% and 2nd line tx in 52%. Overall median DoR was 168 days (95% CI, 132-231 days). Pts with right sided primary tumors and those who received ICI as 1st line tx had longer DoR (p = 0.012 and p = 0.017; respectively). Other aforementioned covariates, including brain mets, had no significant relationship with DoR. Molecular profile (MP) of 592 genes was available for 57 (38.8%) pts. PD-L1 ≥50%, CDKN2A and NOTCH1 mutations were associated with statistically significant longer DoR. Mutations/alterations in EGFR, ALK, ROS1, MET, RET, HER2, KRAS, STK11 and TP53 did not appears to have an impact on the DoR, although some of the analysis was limited because of very small number of pts. Of the 10 super responders, majority had adenocarcinoma, received prior radiation and were current/former smokers. Two had brain mets. Most did not have concurrent use of anti-inflammatory agents (statin or ASA). Only 2 of the super responders had MP available with negative NOTCH1 and CDKN2A mutations. Conclusions: Receiving ICI as 1st line of therapy and having right sided primary tumors predicted longer DoR. Presence of brain mets did not adversely affect the DoR. Super responders were more likely to have adenocarcinoma, prior radiation therapy, and current/former smoking history. PD-L1 expression ≥ 50%, CDKN2A, and NOTCH1 were associated with longer DoR. Presence of actionable genomic alterations, STK11, KRAS and TP53 did not appear to impact DoR to ICI.
Circadian variation in nivolumab efficacy in patients with advanced non-small cell lung cancer.
Authors: Karaboué Abdoulaye , Bisseux Laurence , Pavese Ida , Collon Thierry 
Published: May 2020

e21585 Background: Despite efficacy of human checkpoint inhibitors, only 20 to 30% of treated patients present long term benefits. Circadian variations of the delivery of nivolumab to patients with advanced non-small-cell lung cancer (NSCLC) are proposed here as a factor potentially influencing the efficacy. Methods: A total of 1318 courses of nivolumab were administered in 57 consecutive patients with advanced NSCLC from September 2015 to December 2019 in Medical Oncology Unit of Montfermeil hospital. Percentage of total dose per patient delivered before and after 12:00 pm was computed and corelated to objective response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: Twenty eight patients (49%) received ≥ 50% of their treatment before 12:00 pm (morning group) and 29 patients (51%) after 12:00 pm (afternoon group). ORR was 53.6% in morning group and 31.0% in afternoon group; p = 0.083. Both PFS and OS were significantly longer in morning group as compared to afternoon group. Median PFS was 18.6 months [95%CL, 8.6 – 28.7] and 3.5 months [2.9 – 4.1] in morning and afternoon group respectively; p < 0.001. After a maximum follow-up of 48 months, median OS was not reached in morning group whereas it was 14.4 months [0.0 – 29.5] in afternoon group; p = 0.004. Conclusions: The significant difference in the efficacy of nivolumab between morning and afternoon group is indirect evidence of the influence of circadian rhythm on the metabolism of this checkpoint inhibitor. The application of this finding in clinical practice should allow an increase of nivolumab efficacy in patients with advanced NSCLC.
Genomic heterogeneity of multifocal NSCLC.
Authors: Chen Mingjiu , Ma Haitao , Yu Haoda , Chen Chen , Dai Pingping , He Zhiyi , Li Pengcheng , Zhang Yan , Guan Yan-Fang , Xia Xuefeng , Yang Ling , Yi Xin 
Published: May 2020

e21595 Background: Distinguishing multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IPM) remains a common diagnostic dilemma but critical for developing a therapeutic strategy. Methods: In this study, we analyse genomic features of 584 tissue samples from 258 NSCLC patients with > 1 surgically-resected tumor. NGS was performed using panels of 1021/59 genes. Results: Among 80 patients with definite diagnosis, 23 patients (46 tumors) were diagnosed with IPM. And 57 patients (145 tumors) were MPLC, consisting of 53 synchronous and 3 metachronous tumor pairs. Among 23 IPM tumor pairs, we identified at least one shared somatic mutation. By contrast, 93%(53/57) MPLC tumor pairs exhibited entirely unique mutation profiles in each tumor. Of 57 MPLCs, 4(7%) had no driver alteration ( EGFR, KRAS, BRAF, ALK, ERBB2, MET Exon 14). 9(16%) had a driver in only one of the tumors. In the remaining 44 MPLCs, 40 had unique driver mutation in each tumor. 50%(20/40) had distinct EGFR mutations, the most common combination was L858R and delins in exon 19. Specifically, 8(20%) patients resided ≥3 unique driver mutations simultaneously. This observation indicated that multiple lesions in the same individual can be driven by distinct molecular events. In contrast, 21 available IPM tumor pairs shared the same driver mutation. Pathogenic germline mutations were also analysed. Two were found in 2 MPLCs, involving PLAB2 and BLM, which were both null variants. While there were no pathogenic germline mutations found in IPMs. Regarding the MSI status, all samples from either MPLCs and IPMs displayed MSS, unexpectedly. To further verify the findings above, the remaining 393 samples with uncertain diagnosis were classified into group M (no shared mutation, 218 samples /97 patients) and I (≥1 shared mutation, 175 samples/81 patients). We find the similarity results among all available patients, driver mutation profiles exhibited completely unique and multiple in group M and fully consistent in group I. Conclusions: Taken together, our analyses indicated that the genomic heterogeneity of multifocal NSCLC may be a potential strategy for differentiating IPM and MPLC. This may hold implications for prioritizing therapeutic strategies.
Artificial intelligence model to predict slow progression for advanced non-small cell lung cancer (aNSCLC) patients receiving second-line therapies.
Authors: Charest Francois , Heilbroner Samuel P , Rudeen Karl , Chawla Jitesh , Suryadevara Somasekhar , Narayanan Babu 
Published: May 2020

e21596 Background: There are ongoing efforts to understand and predict exceptional response to existing cancer therapies, but few clinical characteristics of these patients are known. We trained a machine learning model using the Concerto HealthAI database of oncology EMR data that includes clinical data from CancerLinQ Discovery to predict slow progression, a proxy for exceptional response, in aNSCLC in the second line setting. Methods: We trained an XGBoost model to predict patients with a progression free survival (PFS) greater than 180 days from the start of second line therapy (index date). This cutoff approximately determines the top 20% of PFS values in our database (median PFS = 86 days). Patients were included from the study if they (1) were pathologically confirmed aNSCLC without other primary cancer diagnoses and (2) started their second-line therapy between 2013 and 2017. Patients were labeled as slow progressors if they (1) had no evidence of progression or death within 180 days of index and (2) were evaluated for progression for at least 180 days post-index. The model considered data up to 120 days prior to index date. Risk factors in the model included demographics, vitals, common labs, common medical conditions, ECOG performance status, stage, histology, prior cancer treatment patterns, prior progression/response assessments, and medication history. Feature importance was evaluated using SHapley Additive exPlanations (SHAP). Results: 2205 patients met selection criteria of the study. Of these, 420 were labeled as slow progressors. 1776 patients were used for model training and 429 were set aside for model validation. The final model was able to predict slow progression with an AUCROC of 0.75 (F-score 0.48, precision 0.39, recall 0.6). The performance compares favorably to that of a logistic regression model (0.66 AUCROC). Top features that indicated slow progression included a low number of prior progression events or regimens, absence of metastatic disease, lower stage/t-stage/ECOG, absence of COPD, previous treatment with an EGFR inhibitor, normal Alk-Phos/WBC (versus elevated), absence of tachycardia, and a normal BMI (versus low). Conclusions: Machine learning and real world-data provided promising results in predicting slow progression in aNSCLC and may be useful in discovering novel drivers of favorable response.
Biological predictors of third-line treatment outcomes in patients with advanced non-small cell lung cancer.
Authors: Vassias Antonios , Vassos Dimitrios , Grapsa Dimitra , Bakakos Petros , Rovina Nikoletta , Syrigos Konstantinos N. 
Published: May 2020

e21597 Background: The introduction of molecularly-guided targeted therapies and immunotherapy in routine oncology practice has led to significant survival increases in a subset of patients with advanced-stage non-small cell lung cancer (NSCLC). Nevertheless, the ultimate prognosis of these patients remains grim, and their overall therapeutic management challenging, particularly beyond the first-line treatment setting. We herein aimed to assess outcomes of third-line treatment in real-world patients with NSCLC, and to investigate potential correlations of clinicopathological and laboratory fearures with survival data. Methods: The medical records of 111 patients with advanced NSCLC, diagnosed and treated at the Oncology Unit of Sotiria Athens General Hospital between January 1, 2015 and December 31, 2018, were retrospectively reviewed. Eligible patients were those who had received more than two cycles of third-line treatment. Clinicopathological and laboratory features of patients, including baseline levels of complete blood count parameters evaluated immediately before administration of third-line therapy, were recorded and correlated with progression-free and overall survival. Results: The majority of patients had lung adenocarcinoma (54.1%) and stage IV disease (64,9%). Progression-free survival rates at 3 and 6 months were 59% and 20, respectively. Risk of disease progression was 35% lower in adenocarcinoma, as compared to other histological subtypes. Increased haematocrit and reduced white blood cell count levels were independently correlated with decreased risk of disease progression [HR (95% CI): 0,95(0,91-1,00); p = 0,044 and HR (95% CI):.1,05(1,00-1,11); p = 0,048, respectively]. Furthermore, higher white blood cell count and platelet count levels were independent predictors of decreased survival [HR (95% CI): 1,05 (1,01-1,1); p = 0,018 and HR (95% CI): 1,02(1-1,04); p = 0,018, respectively]. Conclusions: Haematocrit, white blood cell count and platelet count, recorded immediately before initiation of third-line therapy, may represent independent predictors of survival parameters in patients with advanced NSCLC.
CONCORDANCE study: An observational, multicenter, prospective study to evaluate concordance of detecting EGFR mutations by circulating tumor-free DNA versus tissues biopsy in NSCLC.
Authors: Prabhash Kumar , Biswas Bivas , Khurana Sachin , Batra Ullas , Biswas Ghanashyam , Advani Suresh Hariram , Mohapatra P , Rajappa Senthill J , Sharma Ajay , Patil Shekar , Dattatreya Palanki Satya , Almel Dr.Sachin , Goyal Gautam , Roy Rakesh , Warrier Narayanankutty 
Published: May 2020

e21615 Background: Epidermal growth factor receptor (EGFR) mutations on circulating tumour free DNA (ctDNA) by liquid biopsy is suitable option in those with difficulty in obtaining tissue samples. Correlation in tissue and plasma results of EFGRm has not been established in the Indian population. 1,2,3 This study was done to investigate the utility of ctDNA for EGFRm testing with Next-Generation Sequencing (NGS) in a real-world diagnostic setting. Methods: This is a multicentre, prospective, diagnostic observational study in 245 newly diagnosed treatment naïve, histologically confirmed, advanced lung adenocarcinoma patients. This was a single visit study. The primary objective of the study was to determine the level of concordance between EGFR mutation status obtained by tissue and ctDNA from blood (plasma) based testing in terms of overall concordance, sensitivity & specificity. Study was registered at Clinicaltrials.gov NCT03562819 & CTRI/2018/08/015290. Results: Seventy-five (30.6%) and eighty-four (34.3%) subjects showed positive mutation status by plasma & tissue testing respectively. The overall concordance of 82.9% was observed between tissue and ctDNA (Plasma) based testing. Sensitivity of EGFR mutation status between ctDNA and tissue was observed for EGFR mutation subtypes was observed to be 100% while specificity was observed to be 90.1%. Plasma and tissue sample testing detected 1.2% (n = 3) and 2.4% (n = 6) positive in exon 20 T790M EGFR mutation, respectively. In terms of secondary outcomes, plasma sample testing detected 16.7% (n = 41) positive for Exon 19 deletions type EGFR mutation followed Exon 21 L858R [11.4% (n = 28)]. Conclusions: CONCORDANCE, a real-world study in Indian patients suggest that ctDNA testing for EGFR mutation analysis is a diagnostic option in newly diagnosed lung adenocarcinoma patients. EGFR Mutation testing in ctDNA, being non-invasive and especially in patients without available/evaluable tumor sample may enable more patients to receive appropriate targeted therapies. [Table: see text]
The impact of prior chemotherapy (PrC) on immunotherapy outcomes in non-small cell lung cancer (NSCLC) patients: Real data from a mono-institutional study.
Authors: Macerelli Marianna , Rizzato Simona , Giavarra Marco , Valent Francesca , Cattaneo Monica , Cortiula Francesco , Targato Giada , Rossetto Ciro , Bozza Claudia , Corvaja Carla , Fioraso Roberto , Fasola Gianpiero 
Published: May 2020

e21639 Background: Immunotherapy has changed the paradigm on NSCLC treatment. No widespread and reproducible predictive biomarkers have been established. We analyzed how PrC could affect ICI outcomes. Methods: We conducted a retrospective observational study and analyzed all NSCLC patients (pts) treated with ICI (nivolumab or atezolizumab or pembrolizumab) in our institution from 2015 to 2018 and followed until January 2020. All pts had received at least one PrC. We recorded clinical features of pts both before and after ICI treatment. Results: A total of 83 pts were included, with a median age of 69 (range, 47-82). Sixty pts (73%) were male, 74 (89%) were smokers and 81 (97%) had ECOG PS 0-1. Thirteen (15.7%) pts had a immune-related toxicity (iRT, G1-G2 76.9% and G3-G4 23.1%) and 21 (25.3%) continued ICI therapy beyond progression disease (PD). Patients with a PD as best response to PrC had more probability to reach a PD with ICI (p = 0.06). Median Progression-Free Survival (PFS) on ICI was 2.9 months (interquartile range, 1.9-9.4) with no statistical difference between pts with oligo- or diffuse progression (≤ or > 5 metastasis) during PrC (p = 0.42). Corticosteroids use was associated with worse PFS (p < 0.01). Median Overall Survival (OS) was 9.1 months (interquartile range, 3.3-26.5), with a benefit for pts with a stable disease (SD) or partial response (PR) to PrC (p = 0.02), for pts who experimented iRT (p = 0.04) and who didn’t receive corticosteroids (p < 0.01). In multivariate analysis liver or brain metastases (HR 8.8, 95% CI 2.9-26.8 and HR 2.2, 95% CI 0.6-8.1), coticosteroids use (HR 3.7, 95% CI 1.3-10.5) or previous cisplatin-based chemotherapy (HR 8.4, 95% CI 2.3-30.1) were associated with worse OS. Instead, pts whit iRT (HR 0.4, 95% CI 0.1-1.3) and PR as best response to PrC (HR 0.8, 95% CI 0.3-2.0) had a better OS. Conclusions: Our study confirms literature data and suggests that PrC could affect ICI outcomes. Tumor burden seems not to influence ICI outcomes, unlike response rate to PrC. Systemic corticosteroids use and iRT predicts ICI outcomes.
Lungful: An observational prospective study to assess the molecular epidemiology of EGFR mutations upon progression on or after first line EGFR-TKI therapy, in real-life clinical settings in Greece.
Authors: Mountzios Giannis Socrates , Mavroudis Dimitrios , Samantas Epaminondas , Koumarianou Anna , Fergadis Evangelos Georgios Konstantinos , Katsaounis Panagiotis , Athanasiadis Ilias , Karamouzis Michalis , Boukovinas Ioannis , Lampaki Sofia , Rapti Aggeliki , Froudarakis Marios E , Kalampaliki Stamatia-Eleni , Anastasopoulou Eleftheria , Somarakis Alvertos , Syrigos Konstantinos N. 
Published: May 2020

e21641 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the gold standard 1st line strategy for non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations (EGFRm), associated with improved survival outcomes and quality of life compared to chemotherapy. Despite the high response rate with first- and second- generation TKIs, most patients develop resistance to treatment and progress. The acquisition of T790M mutation in exon 20 is considered the most common resistance mechanism. This study aims to investigate the molecular epidemiology of EGFR resistance mutations, focusing on T790M in EGFRm NSCLC patients treated with TKIs. Methods: The study included patients with locally advanced/metastatic EGFRm NSCLC who have progressed on or after 1st line treatment with first- or second- generation TKI. Samples either from plasma-based liquid biopsy and/or tissue re-biopsy were analysed using the Cobas EGFR Mutation Test v2. All patients signed informed consent and were enrolled between July 2017 and September 2019. Statistical analyses were performed using SAS software, Version 9.4. Results: Ninety-six eligible patients were enrolled. At the time of progression, T790M mutation was detected in 16.7%of the patients using plasma-based liquid biopsies. Among patients with negative T790M result, in plasma, tissue re-biopsy was performed in 22,7% with evaluable/valid results in 72.2% of them. T790M mutation was identified in 38.5% of re-biopsy samples. According to Cobas EGFR Mutation test results (combined plasma and tissue), T790M mutation was identified in 21.9% of the patients. Of T790M-positive patients 42.9% had previously received first and 57.1% second generation EGFR-TKI. Conclusions: Results from this study in real world clinical setting in Greece, show that EGFR-T790M acquired resistance positivity rate in plasma is lower compared to previous reports. Moreover, these data underline the challenges of implementing precision medicine using tissue re-biopsy in advanced/metastatic NSCLC. Clinical trial information: D133FR00126. [Table: see text]
Molecular characterization and prognostic analysis of non-small cell lung cancer: A single centric real-world study.
Authors: Zhang Hongbin , Wang Yuan , Ji Qiaoxia , Cai Hongmei , Liang Xiangcun , Xie Jiong , Li Hua , Wang Jun , Zhu Guiyun , Tian Erpeng , Zhu Lingling , Yuan Mingming , Wang Kai , Chen Rongrong , Zhao Min 
Published: May 2020

e21646 Background: Identifying targetable genetic variants may help maximize clinical benefit of non-small cell lung cancer (NSCLC). Here, we retrospectively analyzed the benefit of next-generation sequencing (NGS) for NSCLC in routine clinical practice. Methods: A total of 59 NSCLC patients were enrolled in the study from Jun. 2018 to Dec. 2019. Formalin-fixed paraffin-embedded tissues samples were collected and sequenced by NGS, which detects single-nucleotide variants, small insertions/deletions, rearrangements, and copy-number alterations of either 59 or 1021 tumor related genes. The tumor response was evaluated using RECIST v1.1. Results: The detection rate of targetable variants was 59.32% (35/59), including EGFR mutation 49.15% (29/59), ALK rearrangement 5.08% (3/59), ROS1 rearrangement 1.69% (1/59), BRAF V600E mutation 1.69% (1/59), and ERBB2 mutation 1.69% (1/59). Of 29 patients with EGFR mutations, 5 patients (17.24%) had multiple EGFR mutations, including 2 patients (6.89%) with uncommon mutations. 25patients (86.21%) harbored concurrent mutations that may limit the efficacy of EGFR-TKIs, including EGFR amplification, activation of bypass signaling pathways, TP53 exon8 mutation, BCL2L11 deletion polymorphism, and PI3K-AKT-mTOR and cell cycle gene alterations. Among 25 patients received EGFR-TKIs, TKI effectiveness was evaluated in 18 patients. The disease control rate was 100% and overall response rate was 27.78%. The proportion of patients with TMB-H and/or PD-L1≥1, and targetable variants negative was 33.89% (20/59). Only one patient of this group received immunotherapy with pembrolizumab and achieved SD at the 2nd month. The proportion of patients with targetable variants negative, TMB-L, and PD-L1 < 1 or unknow patients was 6.78% (4/59), two patients of them left hospital without additional treatment, two patients received chemotherapy and the KRAS mutation present in one of them suggested that he might be resistant to EGFR-TKIs. Conclusions: More than half of NSCLC patients have targetable genetic variants and more than 30% patients have a molecular signature that can be treated with immunotherapy. Compared with immunotherapy, targeted therapy has higher acceptability in real-world. NGS-based genetic testing may have clinical value to predict the effectiveness of targeted therapy and immunotherapy. It can be widely implemented and standardized into clinical use.