bluuebunny/crossref_metadata_2025 huggingface dataset:
Concurrent TP53 mutation adversely impact the efficacy of crizotinib in ROS1-rearranged lung cancer patients.
Authors: Gen Lin , Xu Huamin , Zhao Jun , Kong Jinliang , Ai Xinghao , Yu Fenglei , Du Kaiqi , Zhu Lingjun , Li Lin , Ma Hongxia , Wang Qiaoli , Xiong Huanhuan , Chen Rongrong , Xia Xuefeng
Published: May 2019

e20535

Background: ROS1 tyrosine kinase inhibitors (TKIs) are now standard of care for patients with advanced ROS1-rearranged NSCLC. But factors that may affect the efficacy of ROS1 TKIs remain to be explored. Methods: We conducted a retrospective multicenter study of lung cancer patients with ROS1 rearrangements. Treatment and survival follow-up was done and clinical records were reviewed. PFS distribution was analyzed by Kaplan-Meier method with log-rank test. Results: In total, we included 94 lung cancer patients with ROS1 fusion genes profiled by next-generation sequencing from May 2016 to September 2018. Fifty of them were female. The median diagnosis age was 54 (25-83). The most common histologic type was adenocarcinoma, which was confirmed in 75 of 78 patients with available pathological results. The most common fusion partners were CD74, EZR, SDC4 and SLC34A2 identified in 42, 19, 12 and 8 patients respectively. Concurrent actionable mutations were uncommon for ROS1 fusion-positive patients. The most frequent concomitant mutated gene was TP53, which was detected in 33% of all the patients. After excluding 29 patients who were lost to follow-up at the very start, the median follow-up time was 8.5 (0-28) months from the moment when mutation profiling was performed. Thirty-nine patients received treatment with crizotinib, among whom 27 were treatment-naïve patients. The median PFS of the 39 patients with crizotinib was not reached yet. Patients with baseline CNS metastasis tend to have shorter PFS compared to patients without (median, 12 vs NR, p = 0.0073). Besides, concurrent TP53 mutations were correlated with worse PFS (median, both NR, p = 0.0417). Mutation profiles of 10 patients were derived from ctDNA testing. No difference was found in PFS between these 10 patients with others whose genomic profiles were based on fresh tissue or FFPE specimens, suggesting that plasma ctDNA serves as good specimen source for mutation profiling to monitor clinical treatment. Conclusions: Concurrent TP53 mutation and presence of CNS metastasis are associated with decreased PFS of ROS1-positive patients treated with crizotinib.
Interim report on CIV recombinant human endostatin in combination with docetaxel/cisplatin (DP)) in comparison to DP in the first-line treatment of phase IIIb/IV squamous-cell NSCLC (JSLCG-001): A multicenter, open-label, randomized phase III controlled study (NCT: 02513342).
Authors: Huang Jian'An , Song Yong , Shi Minhua , Feng Jian , Lv Xuedong
Published: May 2019

e20541

Background: Endostar registration Phase III and post-marketing Phase IV clinical study had confirmed Endostar in combination with Platinum double drugs can improve the NSCLC patients’ outcomes of ORR, PFS and OS. However, It influenced on the patients’ compliance for Endostar day 1-14 intravenous infusion (I.V). Endostar day 1-7 continuous intravenous infusion (CIV) can have the compliance improved obviously. So, we carried out this phase III trial to confirm the efficacy and safety of CIV Endostar in combination with DP regimen for first line treatment of phase IIIB/IV squamous-cell NSCLC. Methods: The planed 188 patients with phase IIIB/IV squamous-cell NSCLC without the history of chemotherapy would be randomly assigned to receive Endostar and DP (Endostar, 15mg/m2/d, civ, d1-7; Docetaxel, 60mg/m2/d, iv, d4; Cisplatin, 75mg/m2/d, iv, d4), or DP (Docetaxel, 60mg/m2/d, iv, d1; Cisplatin, 75mg/m2/d, iv, d1). The cycle was every 3 weeks and 4-6 cycles would be needed in total in each groupl. After 4-6 cycles, CIV Endostar in Endostar+DP group would maintain till PD. The primary end point was PFS. Results: The interim data from 94 cases was included in the analysis. The median PFS in Endostar+DP group was 6.8 months ( 95% CI, 4.0-9.6) versus 3.1 months ( 95% CI, 2.9-3.4) in DP group ( P = 0.024 ). The response rate was 33% in Endostar+DP versus 31% in DP group ( P = 0.838 ). The AEs in each group was comparable. No unexpected AEs in Endostar+DP was found. Conclusions: This preliminary result showed Endostar in combination with DP improved PFS significantly (P = 0.024). Among patients with advanced, previously untreated squamous-cell NSCLC, the longer PFS was related to CIV Endostar on the duration of maintenance. Clinical trial information: NCT02513342.
PD-1/PD-L1 immunotherapy for advanced lung cancer: An electronic medical database based real world study in China.
Authors: Zhao Xiao , Sun Qiong , Sun Sheng Jie , Shi Weiwei , Jiao Shun Chang
Published: May 2019

e20543

Background: Immunotherapy has shown promising results for clinical management of various cancers. We reported our real world experience with PD-1 or PD-L1 immunotherapy in management of advanced lung cancer patients in China. Methods: This is a single-center retrospective study based on the de-identified electronic medical data collected in routine clinical practice. A total of 198 advanced lung cancer (stage IIIA-IV) patients who underwent anti-PD-1/PD-L1 therapy at Chinese People's Liberation Army General Hospital between 2015 and 2018 were included. Progression free survival and overall survival of patients were estimated by Kaplan-Meier methods. The treatment-related adverse events were also analyzed. Results: Median age of patients was 60.0 years (33.0-88.0 years). Most patients were male (150, 75.8%), smokers (116, 61.7%) and had a KPS score ≥70 (169, 97.7%). Of 198 patients, 106 (53.5%) had adenocarcinoma and 54 (17.3%) had squamous cell carcinoma. Thirty-one (15.7%) patients had CNS metastases. Seventy-one (38.8%) patients received two or more prior therapies. Estimated progression free survival was 5.6 months and overall survival was 24.5 months. One-hundred twenty-seven (64.1%) patients had documented to suffer adverse events, most commonly gastrointestinal adverse events and liver damage (Table). Conclusions: Our study showed survival benefits of PD-1/PD-L1 immunotherapy in advanced NSCLC patients in clinical practice. Safety profile was comparable to the previous studies. Our study supports the benefits of PD-1/PD-L1 immunotherapy in clinical management of advanced lung cancer patients. [Table: see text]
miR-200c in extracellular vesicles as a circulating biomarker of EGFR-TKI response and a mediator of EGFR-TKI sensitivity in heterogeneous NSCLC.
Authors: Lin Chienchung , Su Wu-Chou
Published: May 2019

e20547

Background: Through intercellular transfer of EV(extracellular vesicles) miRNA, tumor cells can confer drug resistance to each other and contribute to tumor heterogeneity. However, the mechanisms why EGFR-TKI can be effective in heterogeneous NSCLC with low abundances of EGFR mutations remain unknown. The aim of the study is to investigate the significance of EV miRNA in mediating the efficacy of EGFR-TKI in heterogeneous NSCLC and serving as the biomarker of response to EGFR-TKI. Methods: We first evaluate if EVs from EGFR mutant cell (PC9) can affect EGFR-TKI sensitivity of EGFR wild type cell (CL1-5, H1299) in vitro co-culture system and i n vivo. We then identified the differential miRNA panel by comparing EVs from PC9 to those from CL1-5. Finally, we verified if the expressions level of these miRNA are different in blood EVs from patient with good response compared to those with poor response to EGFR-TKI. Results: We first verified that CL1-5 can take up labelled EVs from PC9 under time-lapse microscope and EGFR mutant DNA can be detected in recipient EGFR wild-type cell using digital PCR. We found EVs from PC9 enhanced gefitinib sensitivity of CL1-5. And co-culturing PC9 with CL1-5 enhanced CL1-5 gefitinib sensitivity which was reversed by adding GW4789, the inhibitor of exosome secretion. In subcutaneous CL1-5 animal model, in comparison to treating with gefitinib or PC9 EVs alone, only the combination treatment with gefitinib and PC9 EVs delayed cancer growth. Using small RNA sequencing, we identified a unique miRNA profile allowing discriminating EV from PC9 cells to those from CL1-5; MiRNA 200 family including 200a, 200b, 200c and mir429 were up-regulated significantly in PC9 EV. From Aug 2015 to Sep 2017, sixteen patients with good response (PFS > 12M) or poor response (PFS < 6M) to EGFR-TKI were enrolled and blood were collected for EV miRNA isolation. Ten of these blood samples were qualified for miRNA analysis and mir200a and 200c were found up-regulated in good responder to EGFR-TKI. The transfection of mir200c in CL1-5 cells not only inhibited the oncogenic pathway contributing to EGFR-TKI resistance including Stat3, Akt, EMT and BIM pathway but also enhanced gefitinib sensitivity of CL1-5 cells. Conclusions: Our data suggested mir200c from blood EV serve as a biomarker of response to EGFR-TKI and mir200c may mediate EGFR-TKI sensitivity in heterogenous EGFR mutant NSCLC.
Peripheral neuropathy among patients with NSCLC undergoing chemotherapy.
Authors: Tyczynski Jerzy Edward , Zhang Dongmu , Bach Bruce Allen
Published: May 2019

e20552

Background: Peripheral neuropathy (PN) occurs in NSCLC patients and may be due to various factors. One of the major factors is chemotherapy treatment. This study assessed the frequency and risk of PN among chemotherapy exposed NSCLC patients. Methods: This retrospective cohort study used the Optum claims in 2015-2017. The main inclusion criteria included: at least 2 diagnosis (Dx) claims for lung cancer; no other systemic cancer Dx within 6 months prior to the NSCLC Dx; at least one line of systemic anti-cancer treatment after the NSCLC Dx; presence of secondary metastatic disease. NSCLC was identified using a published algorithm. PN was identified by at least one claim with ICD-9/ICD-10 PN diagnosis code. Patients were followed from the earliest chemotherapy treatment date until a censoring event (PN Dx, end of enrollment, death, or end of study interval). Descriptive statistics were used to describe demographics; the Cox model and logistic regression were used to analyze risk associated with PN. Results: A total of 5082 patients were identified with an average age of 70.9 years (SD = 8.7) and 52% of male. Most common first line of treatment (LoT) was carboplatin + paclitaxel (31.9%); 32.7% of patients received a 2nd line, 7.6% received a 3rd line, and 1.7% received a 4th or higher line. 857 patients had PN during the follow-up period (16.9%). Median Charlson comorbidity index (CCI) was 1, and mean 1.7 (SD = 1.8). Patients with CCI of 4+ (716 patients) had nearly 60% elevated risk of PN as compared with CCI = 0. Patients with diabetes presented the OR (odds ratio) of 1.58; patients with a history of PN had a higher risk of PN after the initiation of chemotherapy (OR = 3.90). Compared with the PN risk during 1st LoT (reference), the OR of developing PN during 2nd and 3rd+ LoTs was elevated to 1.78 (95%CI 1.49-2.11; p < 0.0001) and 2.61 (95%CI 2.03-3.34; p < 0.0001), respectively. The most common type of PN was sensory neuropathy (33%), then polyneuritis (21%) and diabetic polyneuropathy (18%). Conclusions: PN is common in NSCLC patients. This analysis shows that the risk of PN in NSCLC patients increases significantly along increasing number of LoT. A history of PN and presence of diabetes play an important role as risk factors of PN during anti-cancer systemic treatment.
Understanding biological driver mutations and mechanism of resistance to EGFR-tyrosine kinase inhibitors in lung cancer patients using a novel translational platform.
Authors: Babu Govind K. , Chaudhuri Padmaparna , Koppak Deepak , Biswas Manjusha
Published: May 2019

e20555

Background: Lung cancer causes ~1.69 million deaths globally and 5-year survival rate is < 20%. Surgery is preferred for patients with early stage NSCLC, however, in > 50% cases lung cancers are diagnosed at an advanced stage. EGFR-TKIs, erlotinib and gefitinib have shown benefit in patients harboring sensitizing EGFR mutations, although 20-30% of NSCLC patients do not show good clinical response to EGFR-TKIs despite having the mutations. Several factors have been identified for de novo and acquired resistance to first generation EGFR-TKIs, including secondary mutations such as T790M, aberrant activation of bypass pathways such as amplification of c-MET, or other abnormalities in downstream pathways including KRAS mutations or loss of PTEN among others. There exist significant inter-patient variations in response profiles and mechanisms of resistance, which often confounds treatment selection on a personalized level, especially if first-line therapy fails. Methods: We have developed a patient tumor derived ex vivo platform technology using multi-disciplinary systems biology-based approach that recreates a patient’s tumor microenvironment by preserving the tumor-stromal architecture and immune contexture. Fresh tumor biopsies and 10-ml blood were collected from patients with IRB approval and patient consent. Tumors obtained from 21 lung cancer patients were grown ex vivo on our platform in presence of PBMC and autologous sera. The tumors were treated with standard of care chemotherapies and EGFR inhibitors, and drug efficacy on tumors were measured. Results: Of 18 tumor samples treated with EGFR-TKIs, 4 were predicted responders to gefitinib and 14 were predicted non-responders to EGFR-TKIs (erlotinib or gefitinib). Of the 14 non-responders, 7 were predicted responders to carboplatin/pemetrexed and/or carboplatin/docetaxel. Patients were followed, and clinical data was captured. Whole genome sequencing and mutational analysis was done on the tumors. Hits were validated by immunohistochemical assays. Data from molecular signatures of the tumors with functional, phenotypic assays, were used to delineate mechanism of resistance in individual lung cancer patients to EGFR-TKIs. Conclusions: We have developed an ex vivo, personalized platform, which enables prediction of treatment response on an individual level, and also aids in capturing resistance mechanisms for identifying actionable targets.
Multicenter observational prospective study of nivolumab (Nivo) as 2+ line treatment in advanced refractory NSCLC pts: Clinical and quality of life outcomes.
Authors: Orlova Rashida , Laktionov Konstantin , Bolotina Larisa , Breder Valeriy Vladimirovich , Danilova Anastasia , Filippova Elena , Kornietskaya Anna , Kramchaninov Mikhail , Kushniruk Eugenia , Latipova Dilorom , Ledin Evgeny , Mochalova Anastasia , Moiseenko Fedor Vladimirovich , Nikitina Tatiana , Orlov Sergey , Protsenko Svetlana , Sarantseva Ksenia , Stroyakovskiy Daniil , Zinkovskaya Anna , Ionova Tatyana
Published: May 2019

e20567

Background: We aimed to evaluate clinical and quality of life (QoL) outcomes of Nivo as 2+ line treatment in NSCLC pts within expanded access program and real world practice. Methods: Adult pts with advanced refractory NSCLC were enrolled in 11 centers in RF. All the pts received Nivo 3 mg/kg q2w. Tumor response was assessed using RECIST v. 1.1, adverse events (AEs) – NCI CTCAE v3.0. Patients filled out RAND SF-36 and ESAS-R at baseline, 1, 3, 6 and 12 mos after treatment start. Overall survival (OS) and progression-free survival (PFS) curves were evaluated by the Kaplan-Meyer method and compared by the log-rank test. GEE method was used for QoL analysis; χ2 test – for disease control rate (DCR) comparison. Results: The preliminary analysis was performed in the group of 200 pts with median follow-up 7.4 mos (65% – males; median age – 62 y.o.; ECOG 0-1 – 81%; former/current smokers – 70.5%; non squamous NSCLC – 64%; ≥2 lines of previous treatment – 53%, bone mts – 22%). DCR was revealed in 60.3% pts (108/179 pts, median first evaluation – 2.1 mos); 13 pts died before first response evaluation; 8 pts were not evaluated for response at cut-off. DCR was higher in squamous NSCLC (66%, squamous vs 51%, non squamous; χ2 = 4.0, p = .045). Median OS – 11.5 mos (95%CI 8.3–14.7), median PFS – 4.2 mos (95%CI 3.5–4.9). Patients with poor ECOG (ECOG 2-3 vs 0-1: median OS – 5.6 mos vs 12.4 mos, median PFS – 2.7 vs 4.2 mos) and those with bone mts (with mts vs without mts: median OS – 5.0 vs 12.5 mos, median PFS – 2.8 vs 4.1 mos) had worse survival; log-rank p < 0.05. QoL improved during 6 mos of treatment in more than 50% pts; average increase by 60% of mean Integral QoL Index (IQoLI) at different time-points was observed. Upon GEE, IQoLI improvement during 12 mos was revealed (p < .0001). The severity of fatigue and dyspnea, which had the highest burden at base-line, decreased during 6 mos of treatment in more than 50% and 30% pts, consequently. AEs were registered in 32.7% pts (median of Nivo treatment – 2 mos); among them 17 pts had grades 3-4 AEs; 5 pts – SAEs. Conclusions: Preliminary results of this study support the acceptable efficacy and safety of Nivo in NSCLC pts. Nivo treatment leads to meaningful QoL improvement and decrease of symptom burden in this patient population.
Clinical significance of Ki-67 index expression in advanced non-small cell lung cancer.
Authors: Wang Di ming , Shi Qingming
Published: May 2019

e20576

Background: It is unclear how the Ki-67 index expression affects the objective response to chemotherapy in non-small cell lung cancer(NSCLC). The study analyzed the relationship among the Ki-67 index, the objective response rate and progression-free survival(PFS) of chemotherapy in ad-NSCLC. Methods: 112 patients of advanced NSCLC in our hospital from 2014 to 2017 were studied. Both EGFR and ALK were wild type in adenocarcinoma patients, and no gene test was performed in squamous carcinoma. The relationship among Ki-67 index ,tumor stage, response of chemotherapy and progression-free survival was analyzed by univariate and multivariate analysis.Ki-67 index was used to predict the objective response of chemotherapy by receiver operating characteristic curve(ROC curve). Results: The objective response rate of chemotherapy was 61.6%(69/112);squamous carcinoma was 69.1%(38/55);adenocarcinoma was 54.4%(31/57). Ki-67 index(P = 0.000) and tumor stage(P = 0.025) were the factors influencing the objective efficacy of chemotherapy.Ki-67 index was linearly correlated with tumor stage (r = 0.341,P = 0.001).In the univariate and multivariate analyses, the Ki-67 index was significantly associated with the objective response to chemotherapy (B = -0.069,P = 0.000).Ki-67 index expression can accurately predict the objective response rate of ad-NSCLC chemotherapy by ROC curve(P < 0.0001,AUC = 0.7467,95%CI = 0.6578-0.8356):squamous carcinoma group (P = 0.0003,AUC = 0.8065,95%CI = 0.6922- 0.9208), adenocarcinoma group (P = 0.0193, AUC = 0.681,95%CI = 0.536-0.8262).In the test cohort, the sensitivity of the Ki-67 index to the objective response rate of chemotherapy was 93.02%.In the squamous carcinoma group the sensitivity was 94.12%.In the adenocarcinoma group the sensitivity was 65.54%.The best Cut-off was 55% for the adenocarcinoma group with good chemotherapeutic efficacy and the adenocarcinoma group with poor efficacy. The best Cut-off value was 65% in squamous carcinoma group with good curative effect and squamous carcinoma group with poor curative effect.The overexpression of Ki-67 index was a negative prognostic factor for PFS in ad-NSCLC (P < 0.0001):squamous carcinoma (P = 0.0055), adenocarcinoma (P < 0.0001). In multivariate Cox analysis, Ki-67 index (P = 0.000) and stage (P = 0.001) were negative factors of PFS. Conclusions: Ki-67 index is a clinically significant biomarker in ad-NSCLC, which can predict the objective efficacy of chemotherapy. The high expression of Ki-67 might be an indicator of the shortened PFS time.
PD-1 antibody pembrolizumab administered at non-standard frequency in non-small cell lung cancer (NSCLC).
Authors: Sehgal Kartik , Shea Meghan , McDonald Danielle M. , Huberman Mark , Weiss Glen J. , VanderLaan Paul A , Costa Daniel Botelho , Rangachari Deepa
Published: May 2019

e20617

Background: Pembrolizumab (P) administered every 3 weeks ± chemotherapy is a standard treatment option for advanced NSCLC. However, there have been no post-approval studies to determine the optimal frequency of administration or if longer intervals between administrations are effective. Methods: We conducted a retrospective review of patients with advanced NSCLC treated with P for at least 4 cycles at a single academic center (02/2016-12/2018). Patients received P-based regimens administered at a standard frequency (3 weeks ± 3 days, group A), ≥ 25% of total treatment cycles outside the standard frequency (group B), and < 25% of total treatment cycles outside the standard frequency (group C). We extracted demographic, tumor characteristic, treatment detail and outcomes data. Results: Of 84 P-treated patients, 43 (51%) were identified as receiving at least 4 cycles (groups A: 17, B: 10, C: 16). There were no significant differences in sex, stage at diagnosis, smoking status, tumor histology, driver oncogene mutations, PD-L1 expression, tumor mutation burden, line of therapy, performance status, or immune-related adverse events (irAEs). Patients in group A were more likely to receive P+chemotherapy (groups A: 41.2%, B: 10%, C: 6.3%; p = 0.03). The reasons for non-standard cycles were: patient-physician preference (65.4% patients), irAEs (15.4%), and non-irAE medical issues (42.3%). Time to treatment discontinuation was significantly longer in groups B & C receiving P-based therapy at longer non-standard intervals and with no statistically significant differences in overall survival. Conclusions: Our data, though limited by sample size and single institution design, shows that a significant proportion of patients receive P at extended intervals in routine clinical practice and with comparable outcomes as would be expected for those with advanced NSCLC receiving P at label-specified 3-week intervals. Given the durability of benefit seen in such patients, this requires confirmation in larger datasets and prospective trials so as to maximize patient experience and clinical outcomes while minimizing financial toxicity.
Survival analysis of anticoagulant treatment of non-small cell lung cancer.
Authors: Wang Junyan , Zhang Fan , Hong Lei , Jiang Da , Ma Minting , Wei Suju
Published: May 2019

e20623

Background: More and more evidence shows that coagulation cascade reaction and some vascular factors can promote the deterioration of tumor. Preventive interventions for high-risk patients with venous thromboembolism can reduce cancer mortality and improve quality of life. Anticoagulants have anti-tumor activity and can participate in the process of adhesion, metastasis, invasion, thrombogenesis and immune escape of cancer cells. So we want to explore the effects of anticoagulants on the survival of patients with non-small cell lung cancer. Methods: This study retrospectively analyzed the clinical data of876 cases with non-small cell lung cancer. According to whether or not to apply anticoagulant drugs, it was divided into 2 groups including application group (270 cases) and non-application group (606 cases), and the survival status of the two groups were followed up. Results: The median survival ofthe non-application group was 14.2 months, the 1, 2, 3, and 5 years survival rates of patients were 56.6%, 31.8%, 21.0% and 6% respectively. The application group median survival of the application group was 17.7 months, the 1, 2, 3, and 5 years survival rates of patients were 66.6%, 36.6%, 28.8% and 16.8% respectively. The median OS and survival rate were extended in anticoagulation group compared with another. The overall comparison of the survival curves of the two groups by Log Rank was P = 0.016. Conclusions: Anticoagulant therapy can significantly improve the overall survival of patients with non-small cell lung cancer.
Transcriptional characterization of immune microenvironment and their prediction role for the prognosis of local advanced lung adenocarcinoma.
Authors: Chen Yuqiao , Shi Xinying , Song Xue , Gao Lingling , Mao Beibei , Zhang Henghui , Zhou Yuan , Zhuang Wei
Published: May 2019

e20625

Background: The resection of early stage NSCLC offers patients the best hope of a cure. However, the recurrence rate post-resection remains high. As the mechanisms involved in the process is still not clear due to the unavailability of accurate targets, our study was aimed to integrate the impact of different immune context present in lung adenocarcinoma (LUAD) microenvironment on patients’ prognosis. Methods: RNA targeted sequencing was performed on 24 primary tumor specimens from the resected local advanced LUADs . Transcripts of 395 immune related genes expressed in FFPE tumor samples were analyzed. The limma package was used to analyze the different expressed genes (DEGs) between patients with different prognosis. The gene set variance analysis (GSVA) analysis was performed to explore gene sets enrichment related to the prognosis (PFS, progression free survival) post-resection. Results: 23 DEGs were detected in primary tumor between the better (PFS > 18months, n = 12 ) and worse (PFS≤18months, n = 12 ) prognosis group. The combined prediction model containing MPO, IL-6, CXCR2, FCGR3B, ADGRE5 could identify the favorable prognosis of patients. GSVA and Log Rank test of survival data demonstrated that the antigen processing and lymphocyte activation pathway enrichment may associate with better prognosis (p = 0.01), whereas higher Neutrophils cell infiltration in primary tumor demonstrated a shorter PFS (p = 0.008). Conclusions: In LUAD, the immune related genes such as MPO, IL-6, CXCR2, FCGR3B, ADGRE5, can effectively profile the landscape of tumor immune microenvironment and predict the survival in early stage of lung adenocarcinoma. Accordingly immune pathways were correlated with prognosis of these patients. Our findings suggest that immune-related RNA expression pattern in locally advanced LUAD may provide a potential predictive marker for early recurrence after surgical resection.
Neutrophils lymphocyte ratio role in predicting response to checkpoint inhibitors in metastatic non-small lung cancer.
Authors: Hakim Hosam , Abdalla Ahmed , Hadid Tarik H.
Published: May 2019

e20646

Background: There have been numerous advances in the management of metastatic lung cancer, including targeted therapy against certain mutations in cancer cells and later developing immune therapy with check point inhibitors.From the pre-immune therapy era, a simple blood test allowing the calculation of the neutrophil-to-lymphocyte ratio (NLR) was established as a strong prognostic marker associated with worse overall survival (OS) in several tumor types including non-small cell lung cancer (NSCLC). Methods: We have retrospectively reviewed electronic medical records for patients with Metastatic NSCLC whom received at least one dose of Checkpoint Inhibitors from January 2014 till January 2019 in Van Eslander Cancer Center.The analysis was done using SPSS v. 25.0 and a p-value of 0.05 or less was considered to indicate statistical significance. A univariant analysis was done using Student’s t-test, the Mann-Whitney U test and the chi-squared test. Survival analysis was conducted using Kaplan Meier methodology as well as Cox proportional hazards models. Results: There were 80 patients with metastatic NSCLC received at least one dose of a checkpoint inhibitor. Median age was 63.9 ± 9.3; Males were 45%; Whites were 62.5%. 67.5% of patient had adenocarcinoma and 24% had squamous cell carcinoma. Twenty patients had brain metastasis (25%) and nineteen patients had liver metastasis (24.6%). Eleven patients (13.8%) had PDL-1 greater than 50% and 11 patients (13.8%) had PDL-1 between 1%-50% and 22 patients (27.5%) had negative PD-L1 status. 18.8% received immunotherapy as a first-line treatment and 65% got immunotherapy on their second line and 16.3% had immunotherapy as the third line of treatment or more. Sixty-one patients (76.2%) received Nivolumab and nineteen patients (23.8%) received pembrolizumab. Mean duration of immunotherapy was 13.7 months ± 20.7. Mean NLR was 6.1 ± 5. Patient with NLR > 5:1 had statistically significant higher progression-free survival (PFS) 27.5 months compared to 12 months P = 0.02. Also, Patients with baseline NLR > 5:1 had a trend toward higher median overall survival (OS) but was not statistically significant 41 months compared to 12 months P = 0.08. Conclusions: Our data showed similar finding to Bagley et al and other retrospective analysis from multiple institutes showing that NLR could be a good predictor of response to checkpoint inhibitors And a cutoff of NLR higher than 5.1 was associated with statistically significant better PFS and a trend towards a better OS.
Immune related adverse events in NSCLC patients treated with immune checkpoint therapy who received the influenza vaccination versus no vaccination.
Authors: Reddy Haritha G. , Weis Taylor Mai , Hough Shannon , Daignault Stephanie , Schneider Bryan J.
Published: May 2019

e20657

Background: Influenza vaccination is recommended by the CDC for cancer patients to reduce the risk of influenza-related complications. There is concern that the incidence of immune-related adverse events (irAEs) may be greater in vaccinated patients receiving immune checkpoint inhibitors (ICPI). We sought to interrogate if influenza vaccination in patients with NSCLC receiving ICPI therapy had an increased incidence of irAEs compared to non-vaccinated patients. Methods: We conducted a single-center retrospective analysis of patients with advanced NSCLC who received PD-1 or PD-L1 inhibitor monotherapy between 3/2015 – 12/2018. Influenza immunization records from both institutional and state-wide registries were obtained from 2014 -2019. Comparisons of adverse event incidence between flu vaccinated and control patients were tested using chi-square statistics. Results: 117 patients were included in our analysis, 33 (28%) were vaccinated during ICPI therapy, 19 (58%) received quadrivalent influenza vaccine, 13 (39%) received trivalent influenza vaccine and 1 (3%) was undetermined. 22 (67%) vaccinated patients had an irAE vs 53 (63%) patients who were not vaccinated during ICPI therapy (p = 0.720). 8 (24%) vaccinated patients had an irAE leading to discontinuation of therapy vs 12 (14%) patients who were not vaccinated during ICPI therapy (p = 0.198). The most frequent irAE in both groups was fatigue 16 (48%) vs 28 (33%) (p = 0.128). Notable irAEs included colitis (0 vs 1), pneumonitis (3 vs 3), hepatitis (1 vs 4) in vaccinated patients vs without vaccine, respectively. There were no statistically significant differences in baseline demographics between both groups including age, race, gender, tumor histology or ECOG performance status. Conclusions: Our study suggests that irAEs are not significantly increased with vaccination for influenza during ICPI therapy. However, there is a slight trend toward increased incidence of irAE warranting ICPI discontinuation for which further investigation is needed. Limitations of this study include a small sample size and inability to grade irAE retrospectively.
NTRK1 fusion identified by capture-based next-generation sequencing in non-small-cell lung cancer.
Authors: Zhao Ruiying , Xiang Chan , Dong Nan , Guo Lianying , Ma Shengji , Han Yuchen
Published: May 2019

e20664

Background: The clinicopathological features and genomic rearrangements of neurotrophic tyrosine kinase receptors (NTRKs) fusion in non-small-cell lung cancer (NSCLC) have not been fully identified. To explore NTRK1 fusion in non-small-cell lung cancer (NSCLC) specimens, and to explore the relationships between the NTRK1 fusion and the clinicopathological features and to identify genomic rearrangements by multiple molecular methods. Methods: In total, 3947 NSCLC specimens were tested for NTRK1 fusion using genomic DNA capture-based NGS. Then, these NTRK1 fusion cases were identified by Oncomine Focus Assay and FISH. The clinicopathological features were analyzed. Results: In total, five specimens (0.13%) were detected NTRK1 fusion. All these five specimens were adenocarcinoma (0.15%, 5/3423), while no NTRK1 fusions were found in 496 squamous cell carcinoma (SCC) cases and 28 adenosquamous carcinoma (ASC) cases. The ages of patients carried NTRK fusion were range from 31-year to 64-year-old. These five NTRK1 fusion cases were two females and three males, four non-smokers and one with 30 years smoking history, three surgical specimens and two small biopsies. Among these three surgical specimens, one was minimally invasive adenocarcinoma and two were invasive adenocarcinoma. One canonical fusion (TPM3-NTRK1) was detected, the other four were noncanonical fusion type (C14orf2-NTRK1, RRNAD1-NTRK1, LOC101060524-NTRK1, ARHGEF11-NTRK1). The RRNAD1-NTRK1 case was coexist with L858R mutation of EGFR, and the ARHGEF11-NTRK1 was coexist with G12A mutation of KRAS. All of these five fusions were confirmed by FISH, while only the canonical TPM3-NTRK1 was confirmed by Oncomine Focus Assay. Conclusions: In summary, NTRK1 fusion is rare in lung adenocarcinoma and does not exist in squamous cell carcinoma or adenosquamous carcinoma cases. Age and gender are not significantly correlated with NTRK1 fusion. NTRK1 fusions were more common in non-smokers. Genomic DNA capture-based NGS can detect both canonical and noncanonical NTRK1 genomic rearrangements. Noncanonical NTRK1 genomic rearrangements need confirmed by other methods such as FISH. NTRK1 fusion may coexist with other canonical driver gene mutation.
Effect of body mass index and age on survival in patients with advanced lung cancer treated with anti-PD-1 immune checkpoint inhibitors.
Authors: Richard Corentin , Elkrief Arielle , Malo Julie , Cvetkovic Lena , Florescu Marie , Blais Normand , Tehfe Mustapha , Gagné Andréanne , Orain Michèle , Labbe Catherine , Joubert Philippe , Ghiringhelli François , Routy Bertrand
Published: May 2019

e20676

Background: Age and body mass index (BMI) are important factors in patients treated with chemotherapy. However, in the era of immune checkpoint inhibitors (ICI), the importance of these baseline characteristics is unclear. For example, pooled analysis of age did not influence the clinical response to ICI, whereas patients with BMI > 35 had better outcomes in melanoma and renal cell carcinoma. More data are needed to clarify the role of these two characteristics in non-small cell lung cancer (NSCLC) patients amenable ICI. Methods: We conducted a retrospective analysis of patients treated with anti-PD1 ICI for advanced NSCLC at the Dijon Cancer Center (n = 177), University of Montreal University Hospital (n = 106) and Quebec Heart and Lung Institute (n = 98). BMI and age were considered as continuous or categorical variables. Patients’ baseline characteristics were compared using the Chi-squared test. Survival curves were estimated by the Kaplan-Meier method and compared with the Log-rank test in a univariate analysis. Multivariate cox regression model was used to determine hazard ratios and 95% confidence intervals for progression-free survival (PFS) and overall survival (OS) between the groups, adjusting for other clinicopathologic features. Results: Among 381 patients included, the median BMI was 24.5 (range 16.2-43.4) and 32.7% and 13.6% were classified as overweight or obese respectively. The median age was 66 (range 37-89) and 29% were older than 70 years-of-age. Considering BMI and age as continuous or categorical variables, they were not associated with PFS or OS, with the exception of BMI in the Dijon cohort (continuous: HR = 0.95, 95%CI[0.91-0.99]; < 25 vs > 25: HR = 0.68, 95%CI[0.47-0.99]). Subgroup analysis and multivariate cox regression did not reveal significant interaction of these two factors with outcomes. There was no difference in toxicity between the groups. ECOG performance status was the only significant factor in the three cohorts. Conclusions: Unlike previously described in the era of chemotherapy, obesity and age were not associated with outcomes in NSCLC patients treated with ICI.
Modeling causal associations between frailty components and mortality in older patients with cancer: A structural equation approach.
Authors: Canoui-Poitrine Florence , Martinez-Tapia Claudia , Pamoukdjian Frédéric , Mathoulin-Pélissier Simone , Frasca Matthieu , Paillaud Elena , Bringuier Michael , Brain Etienne , David Jean-Philippe , Laurent Marie , Bastuji-Garin Sylvie , Audureau Etienne
Published: May 2019

e23021

Background: The independent prognostic value of both oncological and geriatric parameters is well-established in older cancer patients. Yet little is known about the causal pathways between them and how they may interact to affect mortality. Using structural equation modeling (SEM), we aimed to assess the direct and indirect impact of geriatric impairments and oncological parameters on mortality in older patients with cancer. Methods: Patients ≥70 years recruited in the ELCAPA cohort for geriatric assessment (GA), between 2007 and 2016, were included. The six following geriatric domains were assessed: function and mobility, nutrition, cognition, mood, comorbidities and polypharmacy, and social support. SEM analysis tested prespecified relationships between geriatric and oncological characteristics (i.e. stage, cancer site and anti-cancer treatment) and their influence on 6- and 12-months mortality following GA. Model fit was assessed through Root Mean Squared Error of Approximation (RMSEA) and Tucker-Lewis Index (TLI). Results: This analysis included 1434 patients (mean age, 80 years (±5.6); female, 48%; 48% metastasis; main localizations: colorectal (19%), upper digestive tract (17%), and breast (17%)). The 6- and 12-months mortality were 56% and 68%, respectively. Significant direct paths to increased mortality were identified for functional impairment (standardized coefficient (SC): 0.37; p < 0.001 and 0.32; p < 0.001), poor nutritional status (SC: 0.11; p = 0.005 and 0.14; p = 0.001) and poor social support (SC = 0.07; p = 0.08 and 0.09; p = 0.02), along with tumor site, metastatic status and anti-cancer treatment. SEM additionally revealed the indirect effects on mortality of comorbidities, cognitive impairment and depression mediated through functional and nutritional status. Model fit was excellent (RMSEA = 0.036, TLI = 0.941). Conclusions: SEM analysis showed the direct effects of functional and nutritional impairments on mortality and also revealed their central mediating role in the indirect impact of comorbidities, depression and cognitive impairment on mortality. Clinical trial information: NCT02884375.
Effects of a personal trainer led exercise intervention on physical activity and physical function of breast cancer survivors.
Authors: Wang Linda F. , Eaglehouse Yvonne L. , Poppenberg Janette T. , Brufsky Jill , Geramita Emily , Zhai Shuyan , Davis Kelliann , Gibbs Bethany , Metz Jason , Van Londen G J.
Published: May 2019

e23053

Background: Regular exercise is an important tool to address physical and emotional effects of breast cancer treatment. However, many breast cancer survivors do not meet minimum recommended levels of physical activity. This study examines effects of a personal trainer led exercise intervention on physical activity levels and physical function in breast cancer survivors. Methods: Women who completed active treatment for breast cancer were recruited from oncology clinics and survivorship programs from September 2015-to September 2017. Subjects were randomized to an immediate exercise or a wait-list control group. The intervention included 3 personal training sessions over a period of up to 30 weeks. Physical activity and function were assessed before and after intervention by pedometer (7-day record) and endurance step test (steps in 2 minutes). Results: 60 women were randomized to immediate intervention (n = 31) or wait-list control (n = 29). Subjects were an average of (mean ± SD) 56 ± 10 years old and 2 ± 1 years since breast cancer diagnosis. At baseline, the exercise group averaged (mean ± SD) 5236 ± 2214 steps/day and 101 ± 23 steps on 2-minute step test while the control group averaged 5856 ± 2916 steps/day and 106 ± 23 steps on 2-minute step test. After intervention, change (mean ∆ ± SD) was 143 ± 1842 steps/day in the exercise group and 79 ± 1862 steps/day in the control group ( p= 0.9). On the 2-minute step test, the exercise group increased 18 ± 20 steps and the control group increased 9 ± 12 steps ( p= 0.07). Conclusions: While there was some improvement in physical function after the personal-trainer led intervention, the short duration and intensity of the intervention may have diminished the effects. Our results suggest a multi-faceted approach may be needed to support significant changes in breast cancer survivors’ physical activity. Future efforts employing a multidisciplinary team, which includes a certified personal trainer, and with larger patient samples may help address this possibility. Clinical trial information: NCT02770781.
Empaglifozin has cardioprotective and anti-inflammatory effects during doxorubicin treatment: A preclinical study.
Authors: Maurea Nicola , Quagliariello Vincenzo , Coppola Carmela , Rea Domenica , Barbieri Antonio , Arra Claudio , Botti Gerardo
Published: May 2019

e23057

Background: Empagliflozin (EMPA), a selective inhibitor of the sodium glucose co-transporter 2 (SGLT2), reduces the risk of hospitalization for heart failure or cardiovascular death in type 2 diabetic patients. We aimed to study if EMPA could have cardioprotective and anti-inflammatory effects in Doxorubicin (DOXO) - Induced cardiotoxicity. Methods: we tested the effects of EMPA alone or in combination with DOXO in HL-1 adult cardiomyocytes evaluating: mitochondrial viability, lipid peroxidation, Leukotriene-B4 expression, p65-NF-κB activation and Interleukin 1β, 8 and 6 secretion. To evaluate cardiac function, Global Longitudinal Strain (GLS) were measured using 2D speckle tracking echocardiography in C57BL6 mice pretreated with EMPA (10 mg/kg/day) per os for 3 days. EMPA was then administered for additional 7 days, alone and in combination with DOXO (2.25 mg/kg/day ip). Cardiac lysates were processed for analysis of pro-inflammatory Interleukins. Results: EMPA, co-incubated with DOXO, is able to increase the cardiomyocyte viability of 33,6 and 82,3 % at 100 and 500 nM, respectively (compared to only DOXO treated cells). EMPA inhibits the lipid peroxidation by decreasing MDA and 4-HNA production of around 23,6 and 28,7 %, at 100 nM and of 47,8 and 52,1 % at 500 nM, respectively, compared to untreated cells. Moreover, EMPA has anti-inflammatory activity with a reduction of Leukotriene B4 expression and p65-NFkb activation of 58,4 and 64,3 % at 500 nM, respectively (compared to only DOXO treated cells). EMPA also decreased the expression of Interleukin 1β (of 28,5 and 68,8 %), Interleukin-8 (of 21,2 and 57,3 % ) and Interleukin-6 (of 28,1 and 49,8 %) at 100 and 500 nM, respectively, compared to only DOXO exposed cells. Preclinically, after 7 days with DOXO, GLS decreased. Interestingly, in mice treated with EMPA+DOXO, EMPA prevents the GLS’s reduction : GLS was 19.24 ± 1.5 (p < 0,01) vs DOXO alone. In DOXO-EMPA groups, the heart IL-1β, IL-6 and IL-8 tissue extract were reduced of 48, 54,4 and 58,2 % compared to only DOXO groups. Conclusions: EMPA has strong anti-inflammatory and cardioprotective effects in DOXO-Induced cardiotoxicity and these effects are mainly mediated by a reduction of the lipid peroxidation, Leukotriene-B4 and NF-κB activation.
Metastatic presentations of previously treated early stage breast cancer patients.
Authors: Itani Najla , Phadke Sneha Deepak , Grogan Nicole , Mott Sarah L
Published: May 2019

e23065

Background: Breast cancer (BC) patients on surveillance often suffer from a fear of recurrence. Given that routine surveillance imaging is not recommended, the ability to recognize metastatic disease early on requires a knowledge of recurrence patterns. The aim of this study was to analyze the most common presentations of metastatic disease. Methods: A retrospective review was conducted of all adult patients at the Holden Comprehensive Cancer Center that were initially diagnosed with early stage BC and later developed metastatic disease, from 2000-2017. Chi-squared tests, and logistic and Cox regression models were used. Results: Of the 2,033 patient charts reviewed, 372 were deemed adequate for analysis. While most metastatic diagnoses were made as a result of reported symptoms (77.6%), 3.2% were made with clinical exam findings and 7.8% incidentally on imaging. Among those with symptoms, musculoskeletal pain was the most common (33.7%) and more frequently noted at scheduled (48.9%) compared to unscheduled visits (26%, p < 0.01). Receptor status was associated with nervous system (NS) symptoms at metastatic diagnosis (p = 0.01), with higher odds of NS symptoms in triple negative (TN) (OR = 3.0) and HER2+ cases compared to ER/PR+ HER2- cases (OR for ER/PR+ HER2+ = 3.5, OR for ER/PR- HER2+ = 3.8). Bone pain was not associated with any specific receptor subtype (p = 0.12). Initial stage and receptor status were associated with time to recurrence (TTR) (both p < 0.01), with stage III disease (versus stage I, HR = 1.60) and TNBC (versus [ER/PR+ HER2-, HR = 2.52) having the shortest TTR. On multivariable analysis, initial stage (p = 0.03), receptor status (p < 0.01), age (p < 0.01), and TTR (p < 0.01) were significantly associated with 10-year survival after metastatic diagnosis whereas the presence of symptoms at metastatic diagnosis was not (p = 0.27). Conclusions: Providers of patients on surveillance for a history of early stage breast cancer should modify their threshold of suspicion for recurrence depending on the characteristics of the initial diagnosis and symptoms subsequently reported. Although most metastatic recurrences were diagnosed by symptoms, patients did not necessarily have a shorter survival as a result of presenting with symptoms.