bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response to afatinib in patients with advanced NSCLC previously treated with reversible EGFR inhibitors in a mono-institutional experience.
Authors: Bennati Chiara , Currà Maria Francesca , Chiari Rita , De Angelis Verena , Minotti Vincenzo , Metro Giulio , Duranti Simona , Molica Carmen , Scafati Chiara , Paglialunga Luca , Pistola Lorenza , Flacco Antonella , Tofanetti Francesca Romana , Siggillino Annamaria , Baldelli Elisa , Ludovini Vienna , Crinò Lucio 
Published: March 2020

e18101 Background: All mutated non-small cell lung cancer (NSCLC) patients (pts) previously treated with an EGFR reversibile inhibitor, develop, soon or later, resistance. Afatinib is a potent irreversible HER family inhibitor, with preclinical data suggesting activity against the resistance mutation EGFR T790M. From August 2005 to January 2011, in a retrospective observational study at our Division of Medical Oncology, we have evaluated 22 advanced NSCLC pts, who have been treated with Afatinib, after disease progression with Erlotinib or Gefitinib. Methods: 22 advanced NSCLC pts who have previously received a reversible EGFR-TKI (gefitinib or erlotinib), and subsequently have been treated with Afatinib in a different setting of their medical history, were included in the analysis. Afatinib was provided in an expanded access program by Boehringer. Results: Patients characteristics: median age 64 ys (34-85); PS 0-1; most of pts were never smokers (82%) with non-squamous histology. 12 pts (54%) had multi-metastatic sites at diagnosis, 4 of which (33%) had brain lesions. Nineteen pts (86%) were found to be EGFR mutated (15 patients with EGFR-sensitizing mutations at exon 19 and 21). No one was K-RAS mutated. Eighteen pts (82%) received Afatinib in a second line TKI setting and 4 pts (18%) in a third line. Overall, 4 pts (18%), 2 of which had a multi-metastatic disease at diagnosis, had a partial response to Afatinib and 11 pts (50%) achieved a stable disease. Of the 16 pts evaluable for response in the second line setting, median progression-free survival (PFS) was 5,2 months. Diarrhea and skin rash were the most common adverse events but a dose-limiting toxicity was observed in only three patients. Conclusions: Our experience confirmed Afatinib clinical activity in patients with acquired resistance to prior reversible TKI. The treatment has been well tolerated and there were no new or unexpected safety findings.
Survival data and toxicity profile in advanced non-small cell lung cancer (NSCLC) patients (PTS) treated within or outside controlled clinical trials.
Authors: Vavala Tiziana , Rovere Giulia , Rapetti Simonetta , Capelletto Enrica , Longo Marina , Giaj Levra Matteo , Crida Benedetta , Novello Silvia 
Published: March 2020

e18103 Background: Even without well defined data, a common perception is that clinical trials inclusion improve outcomes in pts with cancer. We conducted a retrospective analysis, in a single institution, evaluating survival data and tolerability in advanced NSCLC pts treated with standard therapy or within phase II/III clinical trials. Methods: We analysed 300 consecutive pts treated at the Thoracic Oncology Unit at San Luigi Gonzaga Hospital from 2004, January the 1st to 2011, December 31st having these characteristics: histo/cytological diagnosis of NCSLC, stage IV who received at least 3 chemotherapy cycles, minimum follow-up of 6 months. In this pts population 180 (60%) were enrolled in controlled clinical trials (T), while 120 (40%) were treated with standard therapy (S). Results: The most important differences between the two groups were about median age at the time of starting first line treatment (61.2 in group T vs 64 years in group S), pts older than 70 years (19% vs 27%, respectively) and ECOG/PS distribution (PS=2: 0 vs 9 pts, PS=1: 33 vs 53 pts, PS=0: 145 vs 60 pts in T and S group, respectively). Evaluating T and S population: 106 (59%) vs 43 (36%) pts were eligible for second line treatment and 45 (25%) vs 19 (16%) pts for third line treatment. Median OS was 16,3 in T population vs 14,4 months in S population and PFS was 7.1 vs 6.3 months respectively. Any relevant differences was seen between group T and S in terms of toxicity. Conclusions: This single institution retrospective analysis documented a trend of better outcome for pts enrolled in clinical trials compared to those treated with standard therapy (even without a statistical significance) with an higher percentage of pts reaching second and third line therapies. A larger multicenter prospective dedicated trial is needed to have further, more cleaned, data about this item.
Diagnostic and prognostic significance of circulating endothelial cell in advanced non-small cell lung cancer.
Authors: Yuan Dongmei , Lv Yanling , Ma Xingqun , Liu Hongbing , Shi Yi , Song Yong 
Published: March 2020

e18116 Background: The aim of this study was to evaluate the diagnostic and prognostic value of circulating endothelial cells (CECs) during first-line therapy in patients with advanced non-small cell lung cancer (NSCLC). Methods: 102 newly diagnosed advanced NSCLC patients were enrolled in this study. The amount of CECs (CD45- CD31+ CD146+) was enumerated by flow cytometry at baseline and after two cycles of treatment. We correlated CEC counts and the reduction of CECs with objective response rate (ORR) and progression-free survival (PFS). Results: The CECs level was significantly higher in advanced NSCLC patients, ranging from 57 to 1300 cells/105 cells (n=102, mean±SD=299±221 cells/105 cells), than patients with benign lesions (n=35, 205±97 cells/105 cells), and healthy volunteers (n=34, 117±33 cells/105 cells). When the cut off value of CEC counts was 210 cells/105 cells, there was no significant association between CEC counts and OR/PFS of the enrolled patients. However, patients with CECs response after chemotherapy has more chances to achieve OR (P<0.001), and such patients showed longer PFS than those without CECs response (P = 0.041). In the multivariate analysis, the independent prognostic roles of performance status (HR: 3.245, 95% CI: 1.189-8.854), brain metastasis (HR: 3.673, 95% CI: 1.062-12.704), and CECs response (HR: 0.046, 95% CI: 0.188-0.984) were found. Conclusions: The CEC counts could be considered as the diagnostic biomarker for advanced NSCLC patients. And the reduction of CECs after treatment might be more ideal than the CEC counts as a predictive or prognostic factor in patients treated with platinum-based chemotherapy.
A phase I/II clinical trial of intravenous (I.V.) calcitriol with fixed doses of cisplatin and docetaxel in advanced non-small cell lung cancer.
Authors: Ramnath Nithya , Daignault-Newton Stephanie , Dy Grace K. , Muindi Josephia , Adjei Araba , Kalemkerian Gregory Peter , Cease Kemp Bailey , Stella Philip J. , Brenner Dean E. , Johnson Candace S. , Trump Donald L. 
Published: March 2020

e18118 Background: In vitro and in vivo studies have demonstrated the antiproliferative effects of 1, 25 (OH)2D3 (calcitriol) as single agent and antitumor synergy with cisplatin. The goals of this Phase I/II study were to determine the maximum tolerated dose (MTD) of 1, 25 (OH)2 D3 in combination with cisplatin and docetaxel, and to evaluate the efficacy in patients (pts) with metastatic NSCLC.Methods: The study was a multicenter, open-label study in pts with metastatic NSCLC. Pts were adults 18 yrs., PS 0-1 with normal liver/kidney function. For the phase I study, pts (3–6 per cohort) received 1, 25 (OH)2 D3 I.V. every 21 days prior to docetaxel and cisplatin. The starting dose of 1,25 (OH)2D3 was 15 mcg/m2 at sequential ascending dose levels (DL) (15, 30, 60 and 80 mcg/m2) using a 3+3 design targeting a dose-limiting toxicity (DLT) rate of <33%. Docetaxel was administered at 75 mg/m2 and cisplatin 75mg/m2 following 1, 25 (OH)2 D3 for 4 cycles. We analyzed SNPs in the CYP24A1 gene.Results: 37 pts were enrolled (16 in phase I and 21 in phase II) with a median age of 54 (range 34–79) yrs.; M: F, 12:17. At the 80 mcg/m2 dose level, 2/4 pts had DLT of grade 4 neutropenia. There were no cases of hypercalcemia or azotemia. The MTD and recommended Phase II dose was 60 mcg/m2. Among 6 response-evaluable Phase I pts, and 21 phase II pts, there were: 2 confirmed partial responses (PR), 6 unconfirmed PRs and 10 pts with stable disease. The median time to progression was 6.9 months (95% CI 4.4, 12.9) and the median overall survival was 8.3 months (95% CI 5.8, 14.9). Of the CYP24A1 SNPs, the IVS4-308C>G was associated with progressive disease (Chi-Square=0.0062)Conclusions: The MTD of 1,25 (OH)2D3 in combination with docetaxel and cisplatin was 60 mcg/m2 IV every 21 days. Pre-specified endpoint of a 50% response rate was not met in the phase II study. However, disease control in 66% of patients argues for further study of 1,25 (OH)2D3 as maintenance therapy. The CYP24A1 polymorphism IVS4-308C>G may be associated with resistance to a 1,25 (OH)2D3 based therapeutic regimen
Assessment of human papilloma virus in non-small cell lung cancer in never-smokers: A study from a prospective registry of never-smokers.
Authors: Kawaguchi Tomoya , Shimizu Shigeki , Itoh Norimasa , Kubo Akihito , Isa Shunichi , Utsumi Tomoki , Sakaguchi Masahiro , Yoon Hyungeun , Ou Sai-Hong Ignatius , Kitaichi Masanori , Matsumura Akihide 
Published: March 2020

e18126 Background: Driver mutations have been identified in most non-small cell lung cancers (NSCLC) from never-smokers. However, a small percentage of the tumors still have no its mutations detected. Human papillomavirus (HPV) has been hypothesized to contribute to lung carcinogenesis in East Asia. Methods: We started a prospective registry of never-smokers with NSCLC at the Kinki-chuo Chest Medical Center, Japan, in 2008. We consecutively enrolled all the never-smokers after obtaining written informed consent. Among these, we selected the 114 patients treated with surgery to obtain a large amount of DNA. After exclusion of samples with suboptimal quality, DNA was extracted from 93 formalin-fixed paraffin-embedded surgical tissues. HPV genotyping was performed using a PCR-based microarray system for detecting 23 HPV types, including high-risk (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) and low-risk or risk-unknown types (HPV types 6, 11, 30, 34, 40, 42, 53, 54, 61, and 66). Epidermal growth factor receptor (EGFR) and KRAS mutations were examined with real time PCR (genotyping), and EML4-ALK rearrangements were detected using immunohistochemical staining and fluorescence in-situ hybridization. Results: There were 80 female (86.0%) and 13 male patients (14.0%), with a median age of 67 years (range 29-83). Almost all cases were of the adenocarcinoma histological subtype (92.5%). Molecular analysis of these 93 patients detected 59 EGFR mutations (63.4%), 5 K-ras mutations ( 5.4% ) and 4 EML4-ALK rearrangements (4.3%). These abnormalities were mutually exclusive except for one case who had both EGFR and KRAS mutations. HPV 6 was detected in only one case (1.1%), a 49-year-old female who had an EGFR mutation with wild type KRAS and ALK. No others examined were positive for any HPV type. Conclusions: The three driver mutations accounted for 72.0% of NSCLC in never-smokers. Although a low-risk HPV type was evident in one case, no high-risk HPV types were detected in the tumors with or without the mutations. Our results suggest that HPV does not play a major role as the driving oncogenic event in adenocarcinoma in never-smokers in Osaka, the central area of Japan.
Circulating tumor cells and T790M in metastatic non-small cell lung cancer patients with EGFR mutations and acquired resistance to TKI.
Authors: Isobe Kazutoshi , Hata Yoshinobu , Sato Keita , Sugino Keishi , Sano Go , Sakamoto Susumu , Takai Yujiro , Shibuya Kazutoshi , Takagi Keigo , Homma Sakae 
Published: March 2020

e18127 Background: This study assessed correlations between the presence of circulating tumor cells (CTCs), detection of T790M in organs with metastases or circulating-free DNA (cfDNA), and prognosis in metastatic NSCLC patients with acquired resistance to EGFR-TKI. Methods: Metastatic NSCLC patients with activating EGFR mutations, who initially responded but subsequently experienced disease progression while on EGFR-TKI treatment, were defined as having ‘acquired resistance’. Blood samples were collected after development of such acquired resistance and CTCs were counted using the CellSearch system (Veridex). At the same time, T790M in affected organs or cfDNA was analyzed with cycleave real-time PCR assay and fragment analysis. Results: : Six men and 14 women with a mean age of 63.5 yrs (22-84) were enrolled. Histological subtypes were adenocarcinoma in 19 and squamous cell carcinoma in the remaining one. Clinical stages were stage IV in 14 and recurrence with distant metastases after surgical resection in 6. EGFR mutations in tumors at the primary site were G719C in 1, exon 19 deletion in 7, L858R in 10, and G791C + L858R in 2. CTCs were detected in 8 (40%). Numbers of CTCs (per 7.5 ml blood) were 1 in 4 cases, and 3, 4, 8, and 24 in 1 case each. Patients without CTCs survived significantly longer than those with CTCs (≥1 per 7.5 ml). Mean survival time from first detection of CTCs was 3.0 months in patients with CTCs and not reached in patients without CTCs (p < 0.001). T790M was detected in 6 cases (30%). T790M was found in 75% (n = 6/8) of patients without CTCs but in 0% (n = 0/12) of those with CTCs (p < 0.05). Conclusions: The presence of CTCs was correlated with poorly prognosis and lack of T790M in affected organs or cfDNA. The presence of CTCs was informative for distinguishing patients with or without T790M.
Changing causes of death post-epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) era in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Wu Wen Shuo , Chen Yuh-Min , Tsai Chun-Ming , Shih Jen-Fu , Lee Yu-Chin , Perng Reury-Perng 
Published: March 2020

e18132 Background: EGFR-TKIs are effective against tumor EGFR-mutated NSCLC. Patients with tumor EGFR activating mutation (EGFRmu) (exon 19 deletions or exon 21 L958R) had better survival than those with EGFR wild-type tumors (EGFRwt). Many EGFRmu patients have had disease progression with EGFR-TKI treatment due to central nervous system (CNS) metastases, including meningeal carcinomatosis. The objective of this retrospective study is to compare the causes of death in patients with a known tumor EGFR mutation status who had been treated with EGFR-TKIs. Methods: We retrospectively reviewed the chart records of our advanced NSCLC patients who had received diagnosis, treatment, and supportive and hospice care in our hospital between July 2005 and June 2010. Tumor EGFR mutation status was analyzed using the DNA sequence method. All enrolled patients had a documented cause of death. Results: Ninety-four patients had documented tumor EGFR data, had received EGFR-TKI treatment (either erlotinib or gefitinib), and were with or without previous or salvage systemic chemotherapy. Of them, 36 were EGFRwt and 58 were EGFRmu. Overall survival after starting EGFR-TKI treatment was significantly longer in EGFRmu than in EGFRwt patients (median 68.9 weeks vs. 46.3 weeks, p=0.0058). Twenty-nine patients died of CNS metastases and 65 died of organ(s) failure other than the CNS. Patients who died of CNS metastases had undergone EKGF-TKI treatment significantly longer than those who died of other organ(s) failure (median 32 weeks vs. 7.7 weeks, p=0.0003), with a hazard ratio of 2.308 (95% C.I. 1.452-3.668, p=0.0004). A significantly higher proportion of EGFRmu patients died of CNS metastases (26 of 58, 44.8%) than EGFRwt patients (3 of 36, 8.3%) (p<0.001). Conclusions: EGFRmu NSCLC patients survived longer and had a significantly higher probability of mortality due to CNS metastases than EGFRwt patients. This change in the causes of death due to NSCLC was noted after an era of EGFR-TKI treatment, and will have an important impact on the strategies or management of patient supportive and hospice care.
Detection of EGFR and KRAS somatic mutations in tumor tissue and peripheral blood by a liquidchip technology for patients with advanced non-small cell lung cancer.
Authors: Zhang Shucai , Zhang Hui , Yang Xinjie , Li Xi , Qin Na , Xu Jiasen , Yang Huiyi , Zheng Yong-Qing , Yu Gang 
Published: March 2020

e18142 Background: Responsiveness of non-small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitors has been confirmed to relate to mutations in the epidermal growth factor receptor (EGFR) signaling pathway genes. This study’s aim is to detect mutations in two important components of the EGFR signaling pathway, EGFR and KRAS, using a novel liquidchip technology, and to evaluate the correspondence between tumor and plasma DNA in the same patient. Methods: 58 advanced primary NSCLC ( IIIB or ‡W) tumor tissues and matched peripheral blood samples (MPBS) were obtained. The procedures for multiplex PCR, allele specific primer extension (ASPE) and hybridization were performed after DNA extraction. A novel liquidchip platform for simultaneous detection multiple alleles of DNA somatic mutations was applied to detect the EGFR and KRAS status in matched samples. Results: EGFR exon 19 and exon 21 mutation rate was detected to be 29.3% (17/58) and 17.2% (10/58) respectively in tumor tissues, while 20.7% (12/58) and 12.1% (7/58) in MPBS. Among those 27 patients who harbor either EGFR exon 19 or exon 21 mutations in tissues, 19 (70.4%) of them were detected to have the same mutations in their peripheral blood samples. EGFR exon 20 T790M mutations were found in one of the paired samples. All the patients who were detected to have wild-type EGFR in tissues were detected to have wild-type in MPBS as well. In 50 of 58 (86.2%) of the paired samples, the EGFR mutation status in the tumors was consistent with those in the MPBS. The KRAS exon 2 mutation was also found in both blood and tumor samples in one patient; however only in the blood of another patient, not in his tumor. Conclusions: The liquidchip technology may serve as an effective method for detecting multiple gene mutations. EGFR and KRAS gene mutations in blood DNA were highly consistent with the corresponding tissue samples, and therefore, peripheral blood could be used as an alternative sample to predict patients’ response to the anti-EGFR targeted therapy. Further studies to evaluate the clinical application are suggested.
Association of p53 mutations with progression-free survival (PFS) and overall survival (OS) in EGFR-mutated non-small cell lung cancer (NSCLC) patients (p) treated with erlotinib.
Authors: Gasco Amaya , Molina-Vila Miguel Angel , Bertran-Alamillo Jordi , Mayo Clara , Costa Carlota , Gimenez Capitan Ana , Massuti Bartomeu , Camps Carlos , Carcereny Costa Enric , Viteri Ramirez Santiago , Martinez-Bueno Alejandro , Benlloch Susana , Capdevila Laia , Cros Sara , Porta Rut , Cardenal Felipe , Bosch Joaquim , Sanchez Jose Javier , Taron Miquel , Rosell Rafael 
Published: March 2020

e18143 Background: Advanced NSCLC p with EGFR mutations have a median PFS of 14 months (m) and OS of 27 m when treated with erlotinib. In NSCLC cell lines, tyrosine kinase inhibitors (TKIs) induce p53 translocation from the cytoplasm to the nucleus and subsequent upregulation of Fas and caspase activation leading to apoptosis, but this mechanism was defective in p53-null cells. We tested whether TP53 mutations influence outcome to erlotinib in EGFR-mutated p. Expression levels of the p53 repressor MDM2 were also examined. Methods: We assessed p53 status in pretreatment paraffin-embedded tumor samples from 93 erlotinib-treated, EGFR-mutated advanced NSCLC p. Mutations in exons 5, 6, 7 and 8 were screened by High Resolution Melting analysis followed by sequencing of the amplified products with non-wild-type (wt) melt curves. All mutant samples were re-confirmed by standard PCR and sequencing. Expression levels of MDM2 mRNA were determined by quantitative RT-PCR. Results: Mutations in exons 5-8 of TP53 were detected in 26 of 93 p (28%). We found an unusually high frequency of in-frame and frameshift deletions (23% of mutations), indicating that the spectrum of p53 mutations might be different in EGFR-mutated NSCLC. Mutations were less frequent in p with ECOG PS >2 and more frequent in p with the T790M mutation. OS was 15 m in the 16 p with missense mutations 31 m in p with wt p53 and not reached in p with non-missense mutations (P=0.04). PFS was 9 m for 14 p with mutations in one of the p53 DNA binding motifs (DBMs), compared to 19 m for wt p and 27 m for p with non-DBM mutations. MDM2 mRNA levels were significantly lower in tumors with p53 mutations, especially in DBM mutations. In the case of wt p, high MDM2 expression correlated with longer PFS and OS in p with wt p53. Conclusions: TP53 mutations co-exist with EGFR mutations in a significant number of p; missense mutations correlate with shorter OS and mutations in DBMs correlate with shorter PFS. This finding paves the way for the possibility of combining erlotinib with a drug restoring p53 function in those p harboring certain types of mutations in the TP53 gene.
Predicting sensitivity to azacytidine in non-small cell cancer lines by absence of activating mutations.
Authors: Wrangle John , Mohammad Helai P , Abukhdeir Abde , Juergens Rosalyn A. , Harbom Kirsten , Rodgers Kristen , Shin James , Zahnow Cynthia A. , Baylin Stephen , Herman James Gordon , Rudin Charles M. , Brock Malcolm 
Published: March 2020

e18147 Background: A completed clinical trial has demonstrated activity of a combination of epigenetic therapies: entinostat, a histone deacetylase inhibitor, and azacytidine (AZA), a hypomethylating agent. A plasma-based biomarker assaying methylation status of key gene promoters from circulating DNA was developed. In order to test the relationship of activating mutations to sensitivity to epigenetic therapy, we treated non-small cell lung cancer (NSCLC) lines with AZA and assessed tumor growth in xenografts. Tumor from patients on trial was analyzed for mutational status. Methods: Nine NSCLC lines were treated in vitro for 72 hours with 500 nM AZA and injected to form flank tumors in NOG mice. Four lines contain no activating mutations. Of the five mutant lines, three were KRAS and two were EGFR mutations. Lines with no activating mutations are termed “mutation-negative” for known oncogenic drivers. Growth of mock versus treated tumors was compared over time to determine treatment phenotypes. Lines were grouped into four categories: augmented growth compared to mock, no treatment effect, mild inhibition of tumor growth, and marked inhibition. Seventeen tumors from the clinical trial were analyzed by SNaPshot multiplex PCR. Results: Among mutation negative lines three showed marked tumor growth inhibition and one showed mild inhibition. Among cell lines with activating mutations, one showed mild inhibition, three showed no effect, and one showed augmented tumor growth. Among 17 tumor samples from patients on study, four driver mutations were identified: 3 KRAS and one PTEN mutation. All four patients experienced progressive disease on study. Among thirteen patients with mutation negative tumors, three had stable disease and one had a complete response. Conclusions: The association between driver mutation negative status and treatment outcome in NSCLC cell lines in patients receiving AZA and entinostat merits further exploration. Future trials of epigenetic therapy in NSCLC may benefit from a biomarker enrichment strategy and the data presented here represents a potential way forward.