bluuebunny/crossref_metadata_2025_split huggingface dataset:
KRAS mutations as predictive biomarker in patients with EGFR wild-type stage IV nonsquamous non-small cell lung cancer (NSCLC) recruited in a phase II clinical study with carboplatin-docetaxel-bevacizumab.
Authors: Domine Manuel , Izarzugaza Yann , Rojo Federico , Lobo Francisco , Fernandez-Acenero Maria Jesus , Casado Victoria , Rubio Gustavo , Arranz Juan Luis , Leon Ana , Martin-Valades Jose Ignacio , Serrano Gloria , Carames Cristina , Cordova Sharon , Madoz Juan , Zazo Sandra , Rincon Raul , Canadas Carmen , Campos Angel , Perez-Gonzalez Nuria , Garcia-Foncillas Jesus ,   Oncology Department. Hospital Universitario. Fundación Jiménez Díaz. Universidad Autónoma de Madrid. Spain
Published: March 2020

e18069 Background: KRAS mutation are harbored in ~30% of NSCLC patients, and have been described associated with an upregulation of genes involved in angiogenesis, including vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). Bevacizumab (BVZ) is a recombinant monoclonal humanized antibody targeted against VEGF and added to carboplatin-paclitaxel chemotherapy has demonstrated to improve outcome in non-squamous NSCLC. The objectives of this study were to analyze the impact of KRAS mutations in response rate (RR) and time to progression (TTP) in a cohort of patients homogeneously treated with BVZ in combination with carboplatin-docetaxel. Methods: Patients treated with up to 6 cycles of carboplatin (AUC 5), docetaxel (75 mg/m2) and BVZ (7.5 mg/kg) on day 1, every 21 days. Patients with RR or stable disease continued maintenance BVZ (7.5 mg/kg) every 21 days until disease progression. KRAS mutations at codons 12, 13 and 61 were analyzed by COBAS KRAS Mutation Test (Roche) from DNA purified from diagnostic samples. Results: 30 patients were enrolled (24 male, 6 female); median age was 62 years (range 44-82); ECOG 1/2: 22/8. 27 were adenocarcinomas and 3, undifferentiated large cell carcinoma. Smoking habit: 1 non-smoker, 16 current-smoker, and 13 former-smoker. Seven patients were KRAS mutated (23.3%). Carboplatin-docetaxel-bevacizumab therapy showed a significant improved efficacy in KRAS wild-type compared to mutated patients (RR: 85.7% vs 14.3%, p=0.045; and TTP: 9.38 months vs 7.46 months, p=0.033), but did not impact on overall survival (12.4 months in wild type vs 11.06 months in KRAS mutated, p= 0.780). Conclusions: KRAS mutations predict RR and TTP in wild-type EGFR stage IV non-squamous NSCLC patients treated with bevacizumab-based therapy.
Sorafenib (SOR) in advanced non-small cell lung cancer (NSCLC): A phase II study of patient progress after several lines of treatment.
Authors: Vazquez-Estevez Sergio , Varela Silvia , Campos Begoña , Álvarez Elena , Quintero Guillermo , Mel Jose Ramón 
Published: March 2020

e18070 Background: Sorafenib is a potent inhibitor of c-Raf, b-Raf VEGFR-1/2/3 and PDGFR-β. In NSCLC, proliferative signaling through the Ras/Raf/MEK/ERK pathway is often activated from K-ras mutations. Their efficacy as monotherapy to treat advanced NSCLC has been demonstrated in several trials. In them, SOR improved the rate of disease stabilization in patients who had previously been treated with chemotherapy. Our objective is to confirm the clinical and safety results in the daily clinical activity. Methods: Between October 2008 and December 2011, patients with metastatic NSCLC and measurable disease, ECOG 0-1 were treated after having received two or more prior chemotherapy regimens for metastatic disease. SOR was administered at a starting dose of 400 mg bid continuously in 28-day cycles.The primary end points were Overall Survival (OS) and Progression Free Survival (PFS). Survival medians were estimated by the Kaplan-Meier method and comparisons between subgroups were assessed by the log-rank test. Results: Fifteen Caucasian patients were enrolled, with a mean age at diagnosis of 61 (SD = 13.5) years and most of them were males (n = 10, 67%). The predominant histologic type was adenocarcinoma (n = 9, 60%). Twelve (80%) patients were in stage IV at diagnosis. The predominant metastatic sites were lung (n = 8, 53%), lymph nodes, (n = 5, 33%), pleura (n =3, 20%) and bone (n=3, 20%).Patients received a median of 3 (range: 2 to 4) treatment lines prior to the SOR regimen, with a median duration of 80.5 (range: 9 to 247) days.Median OS and median PFS were 98 and 84 days, respectively. No significant differences in survival were found according to gender, smoking, histologic type, stage, metastatic site, ECOG nor presence of biomarkers.The toxicity profile was mild. Adverse events CTC G3/4 were dyspnea (n = 4, 27%), skin toxicity (n = 1, 7%) and vomiting (n = 1, 7%). Conclusions: In this study, patients with metastatic NSCLC receiving SOR had a median PFS of 3 months. The safety profile is acceptable, reversible and manageable without unexpected adverse events to this therapy. While still waiting for the results of ongoing trials, we can say thatSOR is safe, so far, in patients who have been widely treated.
Effect of cancer-associated fibroblasts on cell proliferation and resistance to EGFR-TKI in direct coculture with lung cancer cell lines.
Authors: Lee Jinseon , Choi So-Jung , Kim Jhingook , Kim Sung-Hyun 
Published: March 2020

e18083 Background: Identical lung cancer cells may get diversified depending on tumor microenvironments. We hypothesized that diversity of cancer associated fibroblasts renders identical lung cancer cells various tumor characteristics such as drug responsiveness and proliferation rate. To test this hypothesis, we isolated cancer associated fibroblasts from 20 different lung cancers, and compared their effects on the proliferation and drug responsiveness of lung cell lines. Methods: Cancer associated fibroblasts were isolated from 20 solid tumors of NSCLCs, and treated with Mitomycin to control the overgrowth during cocultures. H358 and A549 cells were mixed with cancer associated fibroblasts in 1:1 ratio and co-cultured for 4-7 days. Cell number was scored by time-lapse photography, and cell morphology was observed under fluorescent microscope. Expression of cell type markers were examined. Responsiveness to Erlotinib was examined in coculture condistions. Results: Cancer associated fibroblasts stimulated cancer cell proliferation ranging from almost no effects to approximately 3 folds. Coculture in transwell with no direct contacts with cancer cells showed minimal stimulatory effects. Direct contacts induced dramatic changes in cancer cell morphology from cohesive epithelial colonies to dispersed fibroblastic single cells. EMT markers such as down-regulation of Cytokeratins and up-regulation of Vimentin were detected in GFP positive cells. A549 cells that were sensitive to 15 uM Erlotinib (IC50=7.5uM) became resistant when co-cultured with cancer associated fibroblasts. Conclusions: In this study, cancer associated fibroblasts isolated from different lung cancers induced significant changes in tumor cell characteristics such as proliferation, EMT, and drug responsiveness.
Safety and efficacy of paclitaxel liposome monotherapy for the treatment of elderly patients with advanced non-small cell lung cancer: A prospective, multicenter, uncontrolled phase II study.
Authors: Ding Zhenyu , Zhou Lin , Lu You 
Published: March 2020

e18086 Background: Recently, a novel form of paclitaxel encapsuled within liposome was developed with increased solubility and a longer half life in vivo. The aim of this study was to evaluate the safety and efficacy of paclitaxel liposome as a single agent chemotherapy for elderly patients with NSCLC. Methods: This study was a prospective, uncontrolled, open-label, multi-center, registered phase II trial (ChiCTR-TNC-00000226).Patients aged over 70 years with metastatic or recurrent non-small cell lung cancer were enrolled. Eligibility criteria included presence of measurable lesions, an ECOG PS of 0-2 as well as adequate organ function. Patients received paclitaxel liposome at an escalating dose of 135mg/m2, 150 mg/m2 and 175 mg/m2 every 3 weeks, and were monitored for safety and efficacy. Results: From 8 participating centers, 42 patients were enrolled with a median age of 73 years (range 70-81). A total of 89 cycles of chemotherapy was administered. No complete response was observed. 6.7%, 14.2% and 7.7% of patients obtained partial response, and 13.3%, 42.9% and 38.5% had stable disease from the escalating dose groups, respectively. The toxicity was mainly neutropenia, thrombopenia and digestive tract toxicity.There were 4 (26.7%), 3 (21.4%) and 3 cases (25%) of grade 3 or 4 neutropenia in the three dose group. Other non-hematological toxicities over grade 3 were rare. Pre-mature cease of chemotherapy occurred in 1 (7.1%) and 2 (16.6%) patients from the dose group of 150 mg/m2 and 175 mg/m2 respectively, all because of persistent toxicity. Median follow-up was 12.4 months (1.0-22.3 months). TTP in three dose group was 1.2 months (95%CI, 1.1-1.3 months), 1.2 months (95%CI, 0.9-1.3 months) and 1.9 months (95%CI, 1.4-2.3 months). Median OS in the dose group of 135 mg/m2 was 4.9 months (95%CI, 1.0-11.5 month), and not reached in the other groups. Conclusions: Paclitaxel liposome administered at the dose of 150 mg/m2 every 3 weeks seems to be safe and effective among these three dose levels. Although the toxicity profile was mild, the overall therapeutic effects were disappoiting.
Circulating endothelial cells and serum caspase-cleaved CK18 to predict for response and survival in non-small cell lung cancer patients receiving endostatin and paclitaxel-carboplatin combined chemotherapy.
Authors: Chu Tianqing , Ding Hao , Gu Aiqin , Pei Jun , Han Baohui , Du Weidong 
Published: March 2020

e18088 Background: Combinations of anti-angiogenic drugs with chemotherapeutics are widely used for cancers control. Whether can better efficacy of such a combinated modality be achieved and predicted earlier is a great challenge. Circulating endothelial cells (CECs) and cytokeratins (CKs) might have a role in tumour angiogenesis and in tumour cell death. Measurement of CECs and CKs in the blood of patients with tumors could be a simple, non-invasive approach to monitor or predict responses and survival to treatment. Methods: One hundred and seven patients with primary advanced non-small cell lung cancer (NSCLC) were enrolled, randomly assigned to either the endostatin treatment group (paclitaxel+ carboplatin+ endostatin) or the control group (paclitaxel+carboplatin). CEC count and serum CK8, caspase-cleaved CK18 (ccCK18) and uncleaved CK18 (CK18) were measured in the 107 subjects at before treatment (baseline), week 3, and week 6 of treatment, respectively. Results: Higher baseline CEC count was observed in patients with good tumor response (p=0.002 for all the 107 patents; p=0.000 in the treatment group). When compared with the baseline level, after 6 weeks therapy in the endostatin group, CECs decreased significantly (p=0.000), but the CKs levels increased. The increased levels of ccCK18 and CK18 at week 6 reached significance in the treatment group (p=0.001 and p=0.048, respectively). Tumor response showed strong correlation with the reduction extent of CECs (p=0.000) and the increase value of ccCK18 (p=0.040) after endostatin therapy. The best cut-off values of the changes of CECs and ccCK18 for prediction of survival were designed being 0.58/ul and 19.6ng/ml, respectively. Furthermore, obvious reduction of CECs and more rise of ccCK18 significantly correlated with the longer median survival (p= 0.013 and p = 0.016 for PFS, p = 0.009 and p=0.012 for OS, respectively). Conclusions: CECs and CKs would be the impressive biomarkers to explore for selecting NSCLC patients who might benefit from endostain in combination with paclitaxel plus carboplatin treatment.
Role of cMET expression in non-small cell lung cancer patients treated with EGFR tyrosine kinase inhibitors.
Authors: Chang Hyun , Zhang Xianglan , Kim Da Rae , Kim Gun Min , Kim Se Hyun , Kim Joo-Hang , Cho Byoung Chul 
Published: March 2020

e18092 Background: We performed this study to investigate whether activation of cMET is associated with sensitivity to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients. Methods: This retrospective study included 69 NSCLC patients with available tumor tissue, treatment response and survival data. cMET and hepatocyte growth factor (HGF) status was evaluated by immunohistochemistry. Results: A positive cMET, cMET[pY1003], cMET[pY1234/1235] and HGF were identified in 89%, 44%, 20% and 89% of cases, respectively. Positive cMET[pY1003] expression was associated with better objective response rate (OR) and clinical benefit rate (CBR) (OR, P = 0.033 and CBR, P = 0.039). Positive cMET[pY1234/1235] was significantly associated with a longer overall survival (OS) (P = 0.012) and time-to progression (TTP) (P = 0.031). Multivariable model confirmed that cMET[pY1234/235]-positive patients had a significant reduction in the risk of death and disease progression than cMET[pY1234/1235] –negative patients [OS; hazard ratio(HR)=0.29, P = 0.008 and TTP; HR=0.43; P=0.024] Conclusions: cMET expression in tumor tissue could be useful for predicting the clinical outcome of EGFR-TKIs treatment. Our results suggest that cMET expression in tumor tissue could be used to refine the selection of NSCLC patients expected to benefit from EGFR-TKIs treatment.
Response prediction by MALDI-TOF-MS serum peptide profiling of combination treatment with sorafenib and erlotinib in patients with non-small cell lung cancer.
Authors: Rovithi Maria , Lind Joline S. , Pham Thang V , Knol Jaco C , Verheul Henk M.W. , Smit Egbert F , Jimenez Connie R. 
Published: March 2020

e18094 Background: Mass spectrometry can be used to generate diagnostic peptide peak profiles "signatures" of serum samples1. Peak profiles can be used to compare different sera and correlate samples (i.e., patient groups) with clinical data to assist in diagnosis, monitoring, and/or prediction. Indeed, in recent studies, we and other researchers have successfully combined serum peptide profiling by mass spectrometry (MS) with bioinformatics and have established distinctive serum polypeptide MS patterns that correlate with cancer types and clinically relevant outcomes2. We performed serum peptide profiling of patients with advanced stage non-small cell lung cancer (NSCLC) treated with erlotinib and sorafenib in a previously reported clinical trial at baseline, after one week of treatment, and after three weeks of treatment, to establish treatment efficacy signatures. Methods: Using automated magnetic C18 bead-assisted serum peptide capture coupled to matrix-assisted laser desorption/ ionization time of flight mass spectrometry (MALDI-TOF MS), serum peptide profiling1 of 50 NSCLC patients was conducted and peptide mass profiles (spectra) obtained. Data analyses of pretreatment serum peptide profiles, as well as dynamic changes in peptide abundance during treatment, were performed to establish support-vector machine-based algorithms that can predict treatment efficacy. Results: A 13 ion-peptide signature could discriminate with a sensitivity of 93% and specificity of 71% a training group of patients with short progression free survival (n=14) and long progression free survival (n=14). The signature shows discriminative power for the remaining non-overlapping set of 22 patients, as well as for the complete dataset of 50 patients. Pattern analysis of overall responses and toxicity is ongoing. Conclusions: Serum peptidome profiling using MALDI-TOF-MS coupled to pattern diagnostics may provide biomarkers predictive of response to targeted treatment in patients with NSCLC, thus enabling pretreatment selection of appropriate subgroups.
Risk of skeletal-related events (SREs) in patients with lung cancer (LC) and newly diagnosed metastases to bone.
Authors: Richert-Boe Kathryn E. , Edelsberg John , Taneja Charu , Lamerato Lois , Glass Andrew , Wolff Greg G. , Czapski Natalie , Chung Karen , Richhariya Akshara , Oster Gerry 
Published: March 2020

e18107 Background: Bone is a common site of metastatic involvement in patients (pts) with LC. Bony metastases (mets) are often associated with SREs (spinal cord compression [SCC], pathologic fracture [PF], surgery to bone [SB], radiotherapy to bone [RT]). Skeletal complications cause significant morbidity and mortality. Current estimates of SRE risk come principally from randomized clinical trials. Information from routine clinical practice is limited. Methods: Using the tumor registry and electronic data stores at a large U.S. Midwest healthcare system that serves approximately 800,000 persons, we retrospectively identified all pts aged ≥18 yrs with primary LC and newly diagnosed bone mets between 1/1/95 and 12/31/09. Electronic medical records were reviewed by trained abstractors for evidence of SREs between date of bone mets diagnosis and death, loss to follow-up, or end of study. Cumulative incidence of SREs was estimated in the presence of competing risk of death. Results: We identified a total of 272 pts with primary LC and newly diagnosed bone mets; 66 pts had evidence of SREs at initial diagnosis of bone mets and were excluded from the analyses. Among the remaining 206 pts, mean (SD) age was 65.7 yrs (10.5 yrs) and 66% were male; 47% were Caucasian and 50% were African-American. Median duration of follow-up after diagnosis of bone mets was 3.0 months (mos). At 6 mos, cumulative incidence of SREs was 45.6% (SCC, 6.9%; PF, 20.6%; SCC and/or PF, 25.0%; SB, 4.1%; RT, 34.7%) (Table). Corresponding figures at 12 mos were 50.8% (SCC, 6.9%; PF, 24.1%; SCC and/or PF, 28.3%; SB, 4.1%; RT, 39.8%). Relatively few pts (17.5%) received intravenous bisphosphonates prior to SRE. Conclusions: Pts with LC in routine clinical practice are at high risk of SREs following initial diagnosis of bone mets. [Table: see text]
EGFR gene mutation and epithelial to mensenchymal transition (EMT) markers in advanced NSCLC patients treated with erlotinib.
Authors: Fidler Mary J. , Dave Manish J , Basu Sanjib , Hensing Thomas A. , Pool Mark , Mahon Brett , Borgia Jeffrey A , Walters Kelly Kaiser , Escarzaga Diana , Batus Marta , Bonomi Philip D. 
Published: March 2020

e18117 Background: TTF-1 is a transcription factor involved in regulating epithelial to mesenchymal transition (EMT). Previous work in a clinically enriched non-small cell lung cancer (NSCLC) population suggested low probability of an EGFR activating gene mutation in the absence of TTF-1 positivity (Somaiah ASCO 2011). This study's goal was to validate the relationship of TTF-1 and other immunohistochemical (IHC) markers of EMT to the presence of an EGFR activating gene mutation in a diverse group of NSCLC patients treated with erlotinib. Methods: Patients receiving erlotinib at two midwest institutions were retrospectively analyzed by IHC for TTF-1 (Greater than 5% of tumor cells with moderate (2+) or strong (3+) nuclear staining considered positive) and for PTEN, Ecadherin,vimentin, beta catinin, and snail (frequency(0-4) times intensity(0-4)). Exon 19 and L858R mutations were detectedusing single-strand conformation polymorphism and sequence-specific polymerase chain reaction (PCR)).Fisher’s exact testand logistic regression wereused to correlate TTF-1(positive or negative) and the remaining EMT markers with the presence of EGFR mutation. Results: 216 patients were analyzed for EGFR activating gene mutations: 15% squamous, 80% smokers. EGFR mutation was found in 11.6% of cases. TTF-1 was present in 8% of squamous cell patients and 71% of adenocarcinoma patients. TTF-1 correlated with prolonged progression free survival (log rank p=.004). TTF-1 positivity was strongly correlated with the presence of mutation (p=.0006, negative predictive value=97.7%). Increasing Ecadherin and increasing PTEN expression by IHC correlated with the presence of EGFR gene mutation when measured on continuum (p=.006 and p=.04, respectively). Conclusions: Though retrospective, our work confirms the negative predictive value of TTF-1 for an EGFR activating gene mutation in a NSCLC cohort representative of a North American population.Though high PTEN and Ecadherin expression also correlated with EGFR mutation, TTF-1 positivity may be a more straight-forward marker that can select patients who should be screened for the mutation prior to initiation of first line therapy.
Clinical significance of hyperpigmentation due to pemetrexed treatment in advanced nonsquamous non-small cell lung cancer in China.
Authors: Hu Qiong , Li Aiwu , Ren Shengxiang , Chen Xiaoxia , Gao Guanghui , Garfield David H. , Zhou Caicun 
Published: March 2020

e18123 Background: Previous publications have demonstrated the efficacy of pemetrexed (PEM) as first-line, second-line and maintenance therapy in advanced non-small cell lung cancer (NSCLC). A recent study found skin toxicities compromised continuation of PEM treatment. The purpose of this study is to investigate the clinical significance of hyperpigmentation (HP) in advanced nonsquamous (NS) NSCLC receiving PEM-based therapy in China. Methods: Medical records of patients with advanced NSNSCLC who received PEM-based treatment in Shanghai Pulmonary Hospital were retrospectively studied. Chi-square test, Pearson’s test as well as Kaplan-Meier method and Cox Proportional Hazards model were performed for statistical analysis. Results: A total of 101 patients were collected with a median age of 58 years old. Among them, 53 (52.5%) were female and 65 (64.4%) were nonsmokers. 52 (51.5%) patients received first-line treatment. Presence of HP was associated with better ORR (22% vs 7.1%, p=0.043) and DCR (84.7% vs 54.8%, p=0.001). Patients with HP had longer PFS (186 days versus 96 days, p<0.0001). There were no significant differences according to grade of HP in ORR, DCR and PFS. There was a higher incidence of hyperpigmentation in patients who received first-line treatment (73.1%% vs 42.9%, p=0.023) and doublet agent (43.1% vs 74.0%, p=0.002). Multivariate analysis demonstrated HP was an independent factor for better clinical outcomes (vs absence, Hazard Ratio [HR] 0.417, 95% Confidential Interval [CI] 0.255-0.690, p=0.001). Conclusions: HP due to PEM is frequent in advanced NSNSCLC receiving PEM. It is an independent predictive factor for better clinical outcomes in Pemetrexed-treated advanced NSNSCLC in China.