bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of gefitinib for advanced non-small cell lung cancer patients with different EGFR mutation types.
Authors: Zhang Haijun , Patel Nishant , Wu Pingping 
Published: September 2018

e20544 Background: The aim of this study was to compare the efficacy and toxicity of gefitinib as first or second line therapy for advanced non-small cell lung cancer (NSCLC) patients with positive exon 21 (L858R) or exon 19 deletion mutation. Methods: We retrospectively analyzed the clinical data of 60 endothelial growth factor receptor ( EGFR) mutated advanced lung adenocarcinoma patients from July 2011 to November 2015, who have received oral gefitinib 250 mg once daily. Gefitinib was taken until disease progression, intolerable toxicity or death. Results: At the time of last follow-up visit, 1 death had occurred. Among the 59 patients who remained survival, 17 patients progressed. Overall, the median progression-free survival (mPFS) was 10 months (95% confidence interval (CI): 7.53–12.46 months, p < 0.05). The response rate (RR) and disease control rate (DCR) were 33.33% and 71.66%, respectively. However, there was longer mPFS in first line therapy than that in second line therapy: in first-line gefitinib therapy, mPFS was 12 months among 41 patients (95% CI: 9.58–14.41 months, p < 0.05); in the second line therapy, mPFS was 7 months among 19 patients (95% CI: 1.31–12.68 months, p < 0.05). Furthermore, in subgroup analyses examining different EGFR mutation types, we noted mPFS was significantly longer for patient with exon 19 deletion than that with positive exon 21in both first line therapy and second line therapy. The most common Grade 1 or 2 adverse events included rash (76.6%), abnormal liver function (60%), dry skin (48.3%), diarrhoea (46.6%), fatigue (40%) and paronychia (33.3%) etcetera in non-haematological toxicity, whereas anemia(33.3%), leukocytopenia (20%) etcetera were included in haematological toxicity. Conclusions: Patients with NSCLC who were selected by positive exon 21 or 19 deletion mutations had significantly longer mPFS in first line therapy than that in second line therapy when treated with gefitinib. And EGFR mutation types may influence the response to gefitinib therapy.
Smad4 expression and chemosensitivity in non-small cell lung cancer.
Authors: Ziemke Michael , Patil Tejas , Nolan Kyle , Malkoski Stephen 
Published: September 2018

e20550 Background: Smad4 is a tumor suppressor that transduces transforming growth factor beta signaling and regulates genomic stability. We previously found that reduced Smad4 expression was associated with increased DNA damage in both human NSCLC and murine NSCLC models and that reduced Smad4 expression inhibits DNA repair and increases sensitivity to DNA topoisomerase inhibitors. In this study, we assessed the association between reduced Smad4 expression and DNA topoisomerase inhibitor sensitivity in human NSCLC as well as the relationship between Smad4 mutation and homozygous deletion and molecular alterations in other DNA repair molecules. Methods: After IRB approval, we retrospectively identified NSCLC patients who received etoposide or gemcitabine and had an evaluable tumor on CT scan at the University of Colorado Hospital between 2004 to 2014. Chemotherapeutic response was quantified by RECIST criteria, while Smad4 expression was assessed by immunohistochemistry (IHC) and quantified on a 0-300 scale. The relationship between Smad4 mutation and other DNA repair molecule alterations was assessed using TCGA data via cBioPortal. Results: Of the 21 evaluable patients, 19/21 received gemcitabine or etoposide for advanced (stage 3 or 4) disease and 10/21 received these agents with concurrent radiation therapy. Reduced Smad4 expression (IHC score < 100) occurred in 8/21 patients and was associated with non-significant trend (p = 0.18, fisher exact test) toward responsiveness to gemcitabine or etoposide. TCGA data analysis revealed that while Smad4 mutation or homozygous loss was not associated with reduced survival, Smad4 alterations were mutually exclusive to defects in DNA repair molecules. Conclusions: Reduced Smad4 expression may be a biomarker for responsiveness to treatment with chemotherapeutic drugs that inhibit DNA topoisomerase, though this study was underpowered to detect this. That Smad4 signaling alterations are mutually exclusive with alterations in other DNA repair machinery is consistent with a role of Smad4 in regulating DNA repair.
Outcome of EGFR mutant patirnts included in a clinical trial after progression on EGFR TKI.
Authors: Pardo Aranda Nuria , Remon Jordi , Martinez Marti Alex , Martinez de Castro Ana Maria , Cedres Perez Susana , Navarro Alejandro , Scheenaard Eulalia , Piera Adelaida , Carbonell LLuisa , Vivancos Ana , Felip Enriqueta , Gámez Córdoba Esther 
Published: September 2018

e20555 Background: EGFR mutant(EGFRm) NSCLC patients develop adquired resistance after 12 months on EGFR TKI. Acquired T790mutation(T790M) is the most common mechanism of resistance in around 60% of patients, followed by MET amplification in 20% of cases. Inclusion in a clinical trials at progression may have an impact in patients’ outcome. Methods: We retrospectively assessed the overall survival in EGFRm patients according to post-progression treatment on 1st/2nd generation EGFR TKI: standard vs. experimental (clinical trial). Also, we assessed the survival in the cohort of acquired T790M NSCLC patients(p). X2 test and long rank test P values are described. OS was defined since progression 1st/2nd generation EGFR TKI to death or last follow up Results: 42p EGFRm were enrolled. According to EGFRm subtype (24 p EGFR del19, 14p EGFR L858R, 1p EGFR exon18, 1 EGFR exon20 ,2p unknown). Median age was 58 (33-83) and 27 (64%) females. First-line EGFR TKI was 30% gefitinib / 58 % erlotinib /10 % afatinib/2% dacotinib At PD, in 51 biopsies (b) were performed,11p were biopsy twice.Tumor tissue for molecular determinations was available in in 86% of cases. Druggable molecular alterations were detected in 57% of cases: 20 acquired T790M and 4 MET amplification. According to these results all 24 p were enrolled in a clinical trial (NCT02108964,NCT01802632,NCT02147990,NCT02335944, NCT02151981), and 18p were screening failure; 8p (45%) of them due to abscense of adquired resistance mechanisms. 10 received platinum-based chemotherapy and 6 only received best supportive care. OS metastatic disease was 51 months for patients included in a clinical trial vs 22 months for those on standard treatment (p < 0.001; 95%CI: 14.4-47). OS was: 34 months vs 10 months for those included in a clinical trial vs standard, respectively (p < 0.001; 95%CI: 8.88-25). For T790M tumours, OS post-progression was 25 months Conclusions: Enrolling patients in clinical trials may allow personalised treatment according to mechanisms of resistance improving survival after 1st/2nd generation EGFR TK progression disease.
Response to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with de novo epidermal growth factor receptor (EGFR) T790M and S768I resistance mutations.
Authors: Kelly Deirdre , Prior Lisa Mary , Gleeson Jack Patrick , McSorley Lynda M. , Kearns Rachel , Brady Claire , Sui Jane Sze Yin , Dawod Mohammed Adam Ibrahim , Burke Louise , McCarthy Julie , McDermott Ray , McCaffrey John , Power Derek Gerard , O'Reilly Seamus , O'Mahony Deirdre , Finn Stephen P. , O'Brien Cathal , Bambury Richard M. 
Published: September 2018

e20557 Background: Patients with synchronous de novo EGFR sensitising and resistance mutations are rare. Little is known about the response of these patients to EGFR TKIs, especially in a Caucasian population. Methods: We identified NSCLC patients found to have EGFR mutations using PCR-based fragment length analysis, mass spectrometry-based genotyping (Sequenom), and Sanger sequencing using a large multi-institutional database. Baseline clinical characteristics, response rate, progression free survival (PFS) and overall survival (OS) were calculated. Results: From 2008-2015, we observed de novo synchronous EGFR sensitising and resistance mutations in 12 patients representing an overall incidence of 3.6% of EGFR mutants and 0.4% of all NSCLC patients tested. Seven patients were treated using EGFR TKI therapy with erlotinib. In all cases, T790M (n = 4,50%) or S768I (n = 4, 50%) occurred concurrently with another sensitising EGFR mutation, either L858R (n = 4, 34%) or exon 19 deletion (n = 8, 66%). Objective responses were seen in two patients (29%). Three further patients had stable disease lasting 6, 23 and 54 months respectively. The median progression-free survival was 24 months and the median overall survival was 34 months. All patients with baseline EGFR S768I mutations (n = 3) had an objective response or stable disease on erlotinib while two of four patients with T790M demonstrated de novo resistance. Conclusions: This is the largest Irish review of synchronous de novo EGFR mutations. The incidence of co-occurring EGFR mutations was 0.4% and erlotinib demonstrated activity in this cohort of patients. Ongoing trials will determine whether next-generation EGFR TKIs such as osimertinib are preferable as first-line therapy in these patients.
Association of the bevacizumab pharmacokinetics with efficacy and toxicity in advanced non-squamous non-small cell lung cancer: Kumamoto Thoracic Oncology Study Group (KTOSG) 1003 study.
Authors: Saeki Sho , Sasaki Jiichiro , Sakata Shinya , Sato Ryo , Saruwatari Koichi , Sakamoto Yasumiko , Inaba Megumi , Kishi Hiroto , Fujii Shinji , Tsumura Shinsuke , Ouchi Mayu , Saito Hideyuki , Hamada Akinobu , Kohrogi Hirotsugu 
Published: September 2018

e20559 Background: Biomarkers predicting the efficacy and toxicity of bevacizumab (Bev) have not yet been established. Therefore we conducted this pharmacokinetic study to elucidate the role of plasma concentration of Bev as a biomarker to predict outcome in the treatment of patients with lung cancer. Methods: This multicenter prospective pharmacokinetic study was conducted among nine centers in Kumamoto Prefecture, Japan. Patients with non-squamous non-small cell lung cancer who were treated using tri-weekly Bev (15mg/kg) with platinum-doublet chemotherapy were enrolled. Plasma samples were collected from all patients before the administration of every dose of Bev until disease progression or treatment discontinuation owing to toxicity. Plasma concentrations of Bev were analyzed via nano-surface and molecular-orientation limited proteolysis coupled with liquid chromatography-mass spectrometry. Results: Between July 2010 and May 2014, 30 patients were enrolled in this study. Majority of the patients received pemetrexed with cisplatin or carboplatin (24 patients, 80%) and others received paclitaxel with carboplatin. The trough concentrations of Bev after first administration (day 22) were 63.19 ± 19.57 μg/mL. Trough concentrations gradually increased until the six cycle of Bev and reached a steady state. Plasma concentrations of Bev did not decrease until disease progression in patients with a long treatment period. Higher mean plasma concentrations of Bev correlated with female sex (p = 0.034) and high serum albumin levels (p = 0.034). Patients who received pemetrexed had higher mean concentrations of Bev (p = 0.038) than those who received paclitaxel. The response rate and progression-free survival did not correlate with the plasma concentration of Bev. Proteinuria (≥Grade 2) correlated with higher concentrations of Bev. Conclusions: Our study demonstrated that various types of chemotherapy influenced the concentrations of Bev, and a higher concentration of Bev may predict the incidence of proteinuria. In addition, clearance of Bev did not change after long treatment period until disease progression. Clinical trial information: 000007630.
Clinical outcomes after whole genome sequencing in patients with metastatic non-small cell lung cancer.
Authors: Tsang Erica S , Shen Yaoqing , Chooback Negar , Ho Cheryl , Jones Martin , Renouf Daniel John , Lim Howard John , Sun Sophie , Yip Stephen , Pleasance Erin , Ma Yussanne , Zhao Yongjun , Mungall Andrew J. , Moore Richard , Jones Steven , Marra Marco , Laskin Janessa J. 
Published: September 2018

e20563 Background: The Personalized OncoGenomics (POG) program at the BC Cancer Agency integrates whole genome (DNA) and RNA sequencing into practice for metastatic malignancies. We examine patients with metastatic NSCLC and report the prevalence of actionable targets, treatments, and outcomes. Methods: Between 2012-2016, 217 patients had a tumor biopsy and blood sample with comprehensive DNA (80X; 40X normal) and RNA sequencing followed by in-depth bioinformatics to identify potential cancer “drivers” and/or actionable/treatable targets. In NSCLC cases, we compared the progression-free survival (PFS) of “POG-informed therapies” with the PFS of the last regimen prior to POG (PFS ratio). Results: In 29 NSCLC cases, median age was 60.2 years (range 39.4-72.6), 11 were male (38%), and histologies were: adenocarcinoma (93%); squamous cell carcinoma (7%). Potential molecular targets (i.e. cancer “drivers”) were identified in 26 (90%), and 21 (72%) had actionable targets. 13 received POG-informed therapies, of which 3 had no therapy before POG. Of 10 patients with POG-informed therapy, median PFS ratio was 0.94 (IQR 0.2-3.4). 3 (30%) had a PFS ratio ≥1.3, and 3 (30%) had a PFS ratio ≥0.8 and <1.3. Conclusions: In this NSCLC cohort, 30% demonstrated longer PFS with POG-informed therapies. Larger studies will help clarify the role of whole genome analysis in clinical practice. [Table: see text]
Outcomes after the diagnosis of brain metastases in Brazilian NSCLC patients.
Authors: Ce Coelho Juliano , Weis Luiza , Marks Patricia , Geib Guilherme , Liedke Pedro Emanuel Rubini , Pereira Rodrigo Perez , Rebelato Taiane , Franzoi Maria Alice B , Branco Mariane , Schwartsmann Gilberto , Azevedo Sergio J 
Published: September 2018

e20568 Background: Brain metastases (BM) are common and affects near half of patients with non-small-cell lung cancer (NSCLC), with poor prognosis. Few data is available about this group of patients and Brazilian are underrepresented. Methods: Patients with NSCLC that developed BM between January 05 and December 15 at Hospital de Clinicas de Porto Alegre were identified and medical records were reviewed. OS and PFS were estimated by Kaplan-Meier curves. Multivariate analysis was performed to identify factors associated with survival. Statistical analysis was performed with SPSS 22.0. Results: 113 patients were identified. Mean age was 60.1 ± 8.7 years, 50% were female, 84% were Caucasian, 87% had a positive smoking history, 71% had adenocarcinoma histology and 72% had stage IV disease at presentation. BM was present at initial diagnosis in 38% of patients. At diagnosis of BM, 39% of patients had a Karnofsky performance status < 70, 20% had systemic disease under control, 31% had more than 3 brain lesions and 81% had a GPA score ≤2. 35 patients (31%) were submitted to either surgery or stereotaxic radiotherapy (SRDT), 52 (46%) to whole brain radiation (WBRT) and 26 (23%) to best supportive care (BSC). With a median follow-up of 11.2 months, 96% of patients have died. The OS was 11.2 months (95% IC, 9.4 to 13.1). The median survival time following diagnosis of BM was 4.9 months and survival according to treatment was 16.3 months for resection, 8.9 months for SRDT, 3.8 months for WBRT and 0.7 months for BSC. A Karnofsky performance status < 70 at diagnosis of BM and palliative treatment to BM (WBRT or BSC) were associated with worse outcome in multivariate analysis. The GPA score wasn't statically associated with prognosis. A longer survival of patients submitted to WBRT was seen when compare to BSC, HR of 0.38. There is a trend for longer survival in patients submitted to BM resection when compared to SRDT, but without statically significance. Conclusions: To our knowledge this is the largest report of NSCLC patients with BM from Latin America. Our data is in line with previous reports. A poor Karnofsky performance status and palliative treatment to BM are associated with poor survival. WBRT is associated with longer survival when compared to BSC in all the GPA score stratus.
IGFBP-7 to confer resistance to the epidermal growth factor receptor tyrosine kinase inhibitor.
Authors: Wu Shang-Gin , Chang Tzu-Hua , Chang Yih-Leong , Tsai Meng-Feng , Yu Chong-Jen , Shih Jin-Yuan 
Published: September 2018

e20572 Background: Lung cancer is a leading cause of cancer death worldwide. The EGFR mutation-positive patients of lung adenocarcinoma had dramatic response to EGFR tyrosine kinase inhibitors (TKIs). However, acquired drug resistance developed invariably after one year treatment course of EGFR TKI. IGFBP-7, a secreted 31 kDa protein, exhibits low affinity for IGF but binds strongly to insulin. No previous studies had been mentioned the correlation between the protein and acquired EGFR TKI resistance. Methods: cDNA microarray was used to screen differentially expressed genes between EGFR TKI-sensitive (PC9 and HCC827) and acquired EGFR TKIs-resistance cell lines (PC9/gef and HCC827/gef). The expression levels of the screened genes were validated by RT -PCR and Western blot analysis. Molecular manipulations (silencing or overexpression) were performed to investigate the effects of IGFBP-7 on gefitinib resistance in vitro. In addition, clinical specimens were collected to validate the imact of IGFBP-7 on the efficacy of EGFR TKI treatment . Results: IGFBP-7 is over-expressed in gefitinib-resistant cells. The IGFBP-7 mRNA expression in the malignant pleural effusion of patients with acquired resistance to EGFR TKI was significant higher than that in the treatment-naïve patients. Knockdown IGFBP-7 reverses gefitinib resistance in PC9/gef cells. Knockdown IGFBP-7 could increase gefetinib induced-apoptosis through the regulation of BIM. IGFBP-7 affected the mechanism of EGFR TKI resistance resulted from inhibition of IGF-IR.. In clinical practice, low IGFBP-7 serum level is associated with longer progression free survival (PFS) of EGFR TKI as the first line treatment. Furthermore, lower IGFBP-7 level of resected tumor predicts a longer 5-year tumor relapse-free survival. Positive IGFBP-7 immunoihistochemical stain could predict a shorter PFS of the first-line EGFR TKI treatment. Conclusions: IGFBP-7 confers resistance to the EGFR TKI and may be a target for future treatment investigation.
ΔCT value of amplified refractory mutation system (ARMS) to predict efficacy of EGFR-TKIs in non-small cell lung cancer: A multicenter retrospective study.
Authors: Liu Laiyu , Chen Min , Li Gong , Yang Dongyong , Xiao Nanjie , Zhang Weijian , Guo Libin , Guan Jian 
Published: September 2018

e20573 Background: This multi-center retrospective study was to determine whether the ΔCt value of Amplified Refractory Mutation System (ARMS) in EGFR mutated detection in tumors predicts the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC). Methods: A total of 108 NSCLC patients harbored an exon 19 deletion (19Del) or exon 21 L858R mutation detected by ARMS were enrolled. We identified patients with ΔCt<1(Group L) harbored a high proportion of EGFR mutation but the patients with ΔCt≥1 (Group H) harbored a low proportion of EGFR mutation in the tumor sample. The progression-free survival (PFS), objective response rates (ORRs) and overall survival (OS) between the groups were analyzed. Results: In the 108 patients we enrolled, 63 were in group L and 45 were in group H. Patients’ demographics and clinical characteristics including age, sex, smoking history, pathology, mutation sites, TNM stage, line of TKIs therapy were not significantly difference between group L and group H. The Median PFS was 331 days (95%CI: 311.8 to 350.2) in group L and 206 days (95%CI, 157.2 to 254.8) in group H and the difference showed statistically significant (P < 0.001). Moreover, the ORRs in group L was significant higher than the group H (60.0% vs 34.9%, P = 0.011). The median OS was 744 days (95%CI, 635.5 to 852.5) in group L and 596 days in group H (95%CI, 491.7 to 700.0) but showed not statistically significant ( P = 0.098). Conclusions: ΔCt value of ARMS in EGFR mutated detection could be an efficacy predictor for EGFR-TKIs treatment in advanced EGFR-mutant NSCLC.
Monitoring of peripheral lymphocyte and neutrophil counts to predict efficacy of nivolumab (nivo).
Authors: Kawashima Yosuke , Nishikawa Shingo , Ariyasu Ryo , Koyama Junji , Saiki Masafumi , Sonoda Tomoaki , Takano Natsuki , Oguri Tomoyo , Kitazono Satoru , Tambo Yuichi , Yanagitani Noriko , Ohyanagi Fumiyoshi , Horiike Atsushi , Horai Takeshi , Nishio Makoto 
Published: September 2018

e20583 Background: Programmed death-1 (PD-1) antibody is a key drug for treating non-small cell lung cancer (NSCLC), but the response rate is about 20% in non-selected populations and efficacy is difficult to predict. We examined correlations between peripheral blood tests, including counts of lymphocytes (Lym), neutrophils (Neu), and C-reactive protein (CRP), and the efficacy of nivolumab (nivo) monotherapy. Methods: Eighty NSCLC patients treated with nivo (3mg/kg every 2 weeks) in our hospital between December 2015 and September 2016 were evaluated. Peripheral blood tests on day (d) 0 (the day before 1st nivo), d15 (the day of 2nd nivo), d29 (the day of 3rdnivo) were evaluated. Absolute counts and the change ratio (%) of Lym, Neu and CRP from baseline (d0) were calculated. Response to nivo was evaluated according to RECIST v1.1. Results: Response to nivo was partial response in 23 cases, stable disease in 13 and progressive disease (PD) in 44 patients (overall response rate, 28%; disease control rate, 45%). Absolute counts of Lym, Neu and CRP at baseline did not differ significantly between non-PD and PD (Lym, 1323/µl vs. 1376/µl; Neu, 4830/µl vs. 5189/µl; CRP, 3.48 mg/dl vs. 3.38 mg/dl). Neu was significantly increased from baseline to d15 and d29 in the PD population compared with the non-PD population (δNeu (d15): 25.2% vs. -6.3%, P= 0.008; δNeu (d29): 16.7% vs. -8.6%, P= 0.006). CRP was also significantly increased from baseline to d29 in the PD population compared with the non-PD population (δCRP: 60.1% vs. -21.2%, P= 0.010). In contrast, Lym was significantly increased from baseline to d29 in the non-PD population compared with the PD population (δLym: 9.6% vs. –6.7%, P= 0.010). Conclusions: Changes in peripheral blood test results after nivo differed between non-PD and PD populations. Monitoring of Neu and Lym and CRP may allow prediction of the efficacy of nivo.