bluuebunny/crossref_metadata_2025_split huggingface dataset:
In silico analysis of DNA damage repair variants in advanced NSCLC patients (pts) to predict response to platinum-based chemotherapy (PBC).
Authors: Karri Saradasri , Stein Matthew K , Patel Kruti , Crawley Melissa , Vontela Namratha Reddy , Alloway Taylor , Morris Lindsay Kaye , Mays John , Hare Felicia , Prouet Philippe , Byrd Kenneth P , Wiedower Eric , Chandler Jason Claud , Fenton Moon Jung , Weksler Benny , Schwartzberg Lee Steven , Martin Michael Gary 
Published: September 2018

e20582 Background: There are no biomarkers that reliably predict benefit from PBC in NSCLC. We hypothesize cancers with DNA damage repair pathway nsSNPs may be more sensitive to PBC. Methods: Pts with advanced NSCLC that received first-line PBC and next-generation sequencing (NGS) with Caris (2013-2015) were retrospectively identified. The total pathogenic burden (SUM) was defined as test-determined pathogenic mutations (Pmut) plus nsSNPs predicted-damaging (pnsSNPs) by in silico analysis with PolyPhen-2 (Harvard). 13 DNA damage repair genes were also selectively analyzed. All p-values were two-tailed. Results: 84 pts were found; 35% female; 58% white, 37% black; median age was 64 (range 26-81); 82% had ≥20 pack-years (py), 12% with < 20 and 6% never-smokers; 27% received immunotherapy (IT) and 5% tyrosine kinase inhibitors (TKI) subsequently. 49 pts had primary progressive disease (58%), 9 stable disease (11%), 16 partial response (19%) and 10 complete response (12%). Median overall survival (OS) was 11 months (1-18). Median SUM was 5 (0-14) with median pnsSNPs 3 (0-11) and Pmut 1 (0-4). For all genes, no link was found between SUM and response (p = 0.95, ANOVA) or OS (p = 0.48, log-rank test). 26 pts (31%) had DNA damage repair lesions (range 1-3) with 33 nsSNPs (23/33 pnsSNPs) and 4 Pmut; genes commonly-mutated were ATM (16), BRCA2 (10) and BRCA1 (5). Race and smoking status did not predict mutation frequency. A trend towards better OS was seen for pts more heavily-mutated in DNA damage repair ( p= 0.01, log-rank test for trend) as > 60% pts with 1-3 nsSNPs survived > 300 days versus < 50% pts with 0. OS was longer for pts with 1+ DNA damage repair lesions (455 days) versus 0 (252 days) [HR 1.81; CI 1.19-3.89; p = 0.01]; no difference in response rate ( p= 0.59, Fisher’s exact) was found. Similar proportions of pts without (16/58; 28%) and with (7/26; 27%) DNA damage repair variants received IT; 4/4 pts TKI-treated had no such lesions. Conclusions: Advanced NSCLC tumors with ≥1 DNA damage repair nsSNP had a superior OS of > 200 days; however, no link with response was found. Further studies are indicated to determine the extent to which DNA damage repair burden can predict benefit in platinum-treated NSCLC pts.
The feasibility of using small biopsy samples from lung cancer for targeted next-generation sequencing.
Authors: Kim Hee Kyung , Ku Bo Mi , Lee Hansang , Heo Mi Hwa , Hong Joo Hyun , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Park Keunchil , Ahn Myung-Ju 
Published: September 2018

e20584 Background: As the genomic based personalized medicine has been advanced, biomarker analysis using targeted next-generation sequencing (NGS) becomes crucial diagnostic approach for treatment of lung cancer. Most patients of lung cancer are diagnosed on small biopsy specimen, but the feasibility of the small tissue samples for targeted NGS has not been evaluated. We aimed to investigate the feasibility of using small tissue samples of lung cancer for targeted NGS. Methods: The medical records of the patients who underwent biopsy and targeted NGS were reviewed. Two types of panel for targeted NGS were used which were AmpliSeq Cancer Hotspot panel v2 and Oncomine Focus Assay. Results: A total of 603 biopsy specimens of lung cancer were analyzed from April 2014 to October 2016. The sites of biopsy were lung or bronchus (51.2%), lymph node (26.2%), Pleura (2.3%), liver (2.5%), Brain (1.7%) and the others (adrenal gland, bone, muscle, spleen, stomach, thymus). Percutaneous transthoracic core needle biopsy (PTCNB) was most frequently used method for acquisition of tissue (24.9%). The other methods of biopsy were bronchoscopy (14.4%), endobronchial ultrasound (EBUS, 23.8%), Video-assisted transthoracic surgery (VATS, 9.9%) and so on. The types of tissue samples were formalin-fixed, paraffin-embedded (FFPE, 80.6%) and fresh tissue (19.4%). All of these samples, 398 cases (66.0%) were successfully analyzed using targeted, NGS. In 34% of analysis failure cases, 23.5% were not adequate for DNA or RNA extraction and 10.5% had amount not to be enough. On multivariate analysis, PTCNB was more likely to fail than other methods of biopsy such as bronchoscopy, EBUS (HR 2.31, 95% CI 1.4-3.8, p = 0.001). Conclusions: The biopsy of lung cancer for targeted NGS was taken from a variety of sites via different methods, and the type of tissue samples was mostly FFPE. Considering the yield of our study, small biopsy specimens could be used to investigate genomic characteristics of lung cancer via targeted NGS.
Activity of an oral hyroxysterol.
Authors: Habib Nabil , Daaboul Hamid Elia , Hage George , Jabbour Abdo , Zeitouni Hind , Khalife Ryiad 
Published: September 2018

e20587 Background: Hydroxysterols are oxygenated derivatives of cholesterol. They have been shown to interfere with proliferation and cause the death of many cancer cell types, such as leukaemia, glioblastoma, colon, breast and prostate cancer cells. They control the transcription and the turnover of the key enzyme in cholesterol synthesis. Hydroxysterols interfere with PI3K/AKT, MAPK/ERK, hedgehog and Wnt pathways of proliferation and differentiation. When administered in vitro to cancer cell lines, hydroxysterols invariably both slow down proliferation and provoke cell death. Many of these compounds show antitumor activity in experimental models and most of them are very toxic. (24-ethyl-cholestane- 3β,5α,6α-triol) is the first oxysterol being tested in the clinic. It is also one of the safest in this class of compounds. Methods: We have treated with this new drug 18 patients suffering from Non-small cell lung cancer (NSCLC); sixteen males and two females. Thirteen had adenocarcinomas and five had squamous-cell carcinoma. The median age was 65. Sixteen patients had a stage IV disease and two had a stage III disease. Seven had a PS: 1, seven had a PS: 2 and four had a PS:3. Seventy-five percent were symptomatic and fifty percent were taking pain killers. Six patients only did not receive previous chemotherapy and five received radiotherapy. Patients received daily 10 mg/Kg of oral (24-ethyl-cholestane- 3β,5α,6α-triol) divided in 3 equal doses, until disease progression. Results: Twelve patients had a partial response (PR), three patients had a stable disease (NC) and three patients had a disease progression (PD). The median duration of response was 8 months but 2 patients are still under treatment. No toxicity was observed so ever. Seventy-five percent of symptomatic patients had a remarkable symptom control. Conclusions: These encouraging results make this new and safe drug a good candidate for further clinical trials either alone or in association with other drugs for the treatment of NSCLC.
MET exon 14 splice site mutation, protein expression, and amplification in pulmonary sarcomatoid carcinoma: A multi-center study from China.
Authors: Chen Xinru , Wang Fang , Xu Chunwei , Sun Wen yong , Gao Fang san , Zhang Yu , Liu Wen xue , Chen Likun 
Published: September 2018

e20595 Background: MET exon 14 splice site mutation (MET exon 14Δ) was identified as a potential driver mutation in non-small cell lung cancer (NSCLC). Previously, several small sample size studies have revealed a higher frequency in pulmonary sarcomatoid carcinoma (PSC) than other types of NSCLC. In order to reveal the accurate frequency of MET gene alterations in Chinese PSCs, we comprehensively studied the frequency and the relationship among MET exon 14Δ, protein expression and amplification in a large cohort of PSCs. Methods: MET exon 14Δ, protein expression and amplification were detected in 148 surgically resected PSC samples from multiple medical centers by using Sanger sequencing, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. Results: MET exon 14Δ was identified in 9 (6.1%) of 148 cases. Six were pleomorphic carcinoma, two were spindle cell carcinoma and one was carcinosarcoma. MET exon 14Δ was more common in pleomorphic carcinoma compared with other subtypes of PSCs (p = 0.01, X2 test) and have an obvious tendency to occur in elder patients. MET protein overexpression was detected in 16.2% (24/148) of PSCs, and was found significantly associated with MET exon 14Δ (p = 0.045). MET FISH positive was detected in 15.5% (23/148), and 6 (4.1%) of them were confirmed as gene amplifications. MET FISH positivity (P < 0.001, X2 test) and amplification (P < 0.001, X2 test) were significantly associated with the IHC positive. No significant relationship between MET exon 14Δ and amplification was found. Conclusions: Chinese PSC has high incidence of METexon 14Δ and amplication. MET inhibition may benefit this specific subgroup of patients.
Prognostic prediction of pemetrexed-platinum chemotherapeutic regimen for NSCLC by serum metabolomics.
Authors: Wang Jie , Tian Yanhua , Wang Zhijie , Bai Hua , Duan Jianchun 
Published: September 2018

e20603 Background: Pemetrexed-platinum chemotherapeutic doublet has become a standard schedule as the first-line treatment for advanced non-squamous NSCLC due to its promising efficacy and a favorable toxicity profile. However, chemotherapy resistance inevitably limits the therapeutic effect of this preferred chemotherapeutic regimen, especially for these intrinsically resistant patients. Development of predictive biomarkers to identify those patients who can benefit from this pemetrexed-based regimen has great significance for personalized chemotherapy. Methods: Total 354 patients who were diagnosed with inoperable stage IIIB or IV lung adenocarcinoma (LADC), assigned to receive pemetrexed-platinum doublet chemotherapy as the first-line treatment were enrolled into this prospective study, including 251 cases diagnosed ahead as training set for predictive model establishment and the subsequently diagnosed 103 cases into validation set. Ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS) analytical platform were applied to perform the metabolic profiling studies of pre-treatment serum samples. Results: In the training set, eight potential biomarkers, comprising of hypotaurine, taurine, choline, betaine, dimethylglycine, uridine, dodecanoylcarnitine and L-palmitoylcarnitine, were discovered to be differentially expressed between the patients in disease progressive group (PD, n = 53) and disease control group (including CR, PR and SD, n = 198). In the validation set (PD vs non-PD: 23 vs 80), targeted quantitative analysis of these metabolic biomarkers revealed similar levels as that observed in the training set. Logistic regression model was accordingly established based on this eight-metabolic biomarker panel, to discriminate patients who might benefit from this chemotherapy regimen with over 90% accuracy. Conclusions: This prospective study identified blood-based biomarker panel by metabonomics analysis could predict the clinical outcome of pemetrexed-platinum chemotherapy prior to treatment for LADC patients, which needed to be validated by clinical trials of large samples.
A phase I/II study of pembrolizumab (P) with gemcitabine (G) in patients (Pts) with previously-treated advanced non-small cell lung cancer (NSCLC): Phase I safety results.
Authors: Sanborn Rachel E. , Duffy Regan M. , Fisher Brenda K , Perlewitz Kelly Shea , Redmond William L , Koguchi Yoshinobu , Fox Bernard A. 
Published: September 2018

e20605 Background: P, an anti-PD1 antibody active in advanced NSCLC, has optimal benefit in tumors with high PD-L1 expression. G may increase antigen cross-presentation and prime CD8 T cell responses via increased tumor cell apoptosis. The combination of antigen cross-presentation and T cell activation may have a synergistic effect with concurrent anti-PD1 immunotherapy. This study is evaluating P + G in pts with previously-treated advanced NSCLC with goal to establish feasible dosing prior to phase II evaluation. Methods: The phase I portion enrolled sequential cohorts of 2 pts each with advanced NSCLC (1-3 prior lines of therapy), regardless of PD-L1 status. Treatment consisted of G, 1250 mg/m2, Days (D) 1 & 8 + P 200 mg D 1; 21-day cycles. Pts received G to max 6 cycles, P to max 2 years. Each cohort closed until pts completed 6 weeks therapy (2 cycles). Dose limiting toxicity (DLT) was defined as Gr 4 hematologic or Gr 3/4 non-hematologic toxicity at least possibly treatment-related within the first 6 weeks. Dose de-escalation would occur if ≥ 2 related DLTs occurred in the first 6 pts (accrual 6-36 pts); de-escalation was allowed for each drug independently based on toxicity attribution. Tumor tissue was collected for central PD-L1 testing and immune score analysis. Exploratory analysis of immune response via protein array and whole blood immunophenotyping is pending. Results: 6 pts were enrolled. Male/Female: 2/4; Age 53-73 (Median 67.5); ECOG 0/1: 1/5 pts, respectively. Median prior lines of therapy: 1 (Range 1-3). DLT: Gr 4 pulmonary hemorrhage with respiratory failure (1 pt, related to G). Other toxicities in DLT period: Gr 3 neutropenia (1), anemia (2 events in 1 pt). Other toxicities were Gr 1/2. 1 pt developed Gr 3 pneumonitis after DLT period ended (after cycle 3) and was removed from study treatment. Median cycles: 4 (Range 2-8). Primary reason for discontinuation was progression (4 pts). PD-L1 results by central analysis are pending. Conclusions: 1 DLT was observed in phase I; de-escalation was not triggered and the combination is considered feasible for phase II evaluation with G 1250 mg/m2 and P 200 mg (enrolling). Clinical trial information: NCT02422381.
A phase II trial of carboplatin plus S-1 for elderly patients with advanced non-small cell lung cancer with wild type EGFR (OLCSG1202).
Authors: Bessho Akihiro , Ochi Nobuaki , Kuyama Shoichi , Fujimoto Nobukazu , Umeno Takahiro , Ninomiya Kiichiro , Ikeda Genyo , Harada Daijiro , Kishino Daizo , Hosokawa Shinobu , Chikamori Kenichi , Nogami Naoyuki , Harita Shingo , Ueoka Hiroshi , Hotta Katsuyuki , Takigawa Nagio , Tanimoto Mitsune , Kiura Katsuyuki ,   Okayama Lung Cancer Study Group
Published: September 2018

e20614 Background: S-1 is an oral fluoropyrimidine anticancer agent that combines tegafur, gimeracil, and oteracil potassium. Two phase III trials in advanced non-small cell lung cancer (NSCLC) showed the non-inferiority of combination of S-1 with carboplatin or cisplatin compared with standard platinum doublet chemotherapy. Although the S-1/platinum is one of the first line combinations for advanced NSCLC, efficacy and safety of the regimen in the elderly remain unknown. Methods: Patients were required to be previously untreated advanced NSCLC with wild-type EGFR, aged 70 or more, PS of 0-2. They received oral S-1 (40 mg/m2, twice daily) for 2 weeks and carboplatin (AUC 5 on day 1) every 4 weeks as an induction treatment. After 4 cycles of the induction, S-1 alone (40 mg/m2, twice daily for 2 weeks) was administrated every 4 weeks as a maintenance therapy until PD. Primary endpoint was overall response rate (ORR), which was expected more than 20%, and secondary endpoints included disease control rate (DCR), PFS, OS, and toxicity profile. The association between clinical outcomes and gene expressions including thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, orotate phosphoribosyl transferase, VEGF and ERCC1 in tumors was evaluated. Results: Thirty-three patients were enrolled between March 2013 and June 2015. Median age was 78 years old (range: 70 – 89), and 51.5% had a PS of 0. ORR was 30.3% (95% CI: 14.6 – 46.0%) and DCR was 57.6% (95% CI: 40.7 – 74.4%). Grade 3/4 toxicities included thrombocytopenia (42.4%), neutropenia (33.3%) and anemia (27.3%). There was one treatment-related death due to aspiration pneumonia following febrile neutropenia. Median PFS and OS times were 134 days (95% CI: 79 – 173) and 479 days (95% CI: 250 – 571), respectively. Low thymidine phosphorylase expression was associated with DCR (P < 0.01). Conclusions: Carboplatin plus S-1 showed preferable efficacy and tolerable toxicity for elderly with NSCLC. (Clinical trial number: UMIN000009345) Clinical trial information: 9345.
Metabolic activity by 18F-FDG-PET/CT to predict for early response after nivolumab in previously treated NSCLC.
Authors: Kaira Kyoichi , Naruse Ichiro , Higuchi Tetsuya , Alltan Bolag , Mogi Akira , Shimizu Kimihiro , Sunaga Noriaki , Hisada Takeshi , Asao Takayuki 
Published: September 2018

e20615 Background: Nivolumab, an immune checkpoint inhibitor and approved as an anti PD-1 drug, is administered to patients with previously treated non-small cell lung cancer (NSCLC). However, there are no established biomarkers to predict the efficacy of nivolumab. Here, we report a prospective study to investigate whether 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) can predict therapeutic response after early-phase nivolumab treatment. Methods: Twenty-four patients who received nivolumab were enrolled from January to September 2016. 18F-FDG-PET/CT was performed before and 1-month after nivolumab therapy. SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated in comparison with CT scan. We also analyzed the protein expression of PD-L1 and identified tumor infiltratrating lymphocytes (TILs) such as CD4-, CD8-, and Foxp3-positive cells within tumor specimens by immunohistochemistry. Correlation of response and nivolumab plasma concentration 1-month post therapy was analyzed. Results: Among the 24 patients, an early metabolic response to nivolumab was observed in 7 patients (29%) on SUVmax, 6 patients (25%) on MTV, and 8 patients (33%) on TLG, whereas 7 (29%) patients achieved a partial response (PR) by RECIST. Out of the 7 patients with confirmed PR, early metabolic response by SUVmax, SUVmean, MTV, and TLG were observed in 6 (85.7%), 5 (71.4%), 5 (71.4%) and 7 (100%) patients, respectively. However, only one patient (14.2%) yielded a PR by CT scan 1-month after nivolumab. All 9 (100%) patients with progressive metabolic disease by TLG had confirmed progressive disease (PD). Progression-free survival of more than 5 months was observed in all patients with early metabolic response by TLG. The morphological change by CT scan was not clearly identified as an early response. No significant correlation was found between metabolic response and nivolumab plasma concentration and expression of PD-L1 and TILs. Conclusions: Metabolic response calculation by TLG could be a better early-phase predictor of efficacy and survival after nivolumab in comparison with immune biomarkers such as PD-L1. Clinical trial information: UMIN000020814.
Feasibility and outcome of repeat biopsy upon progression on tyrosine kinase inhibitors in patients with EGFR mutation positive adenocarcinoma of lung-an Indian tertiary cancer centre experience.
Authors: Zanwar Saurabh , Noronha Vanita , Joshi Amit , Patil Vijay Maruti , Chougule Anuradha , Janu Amit , Kumar Rajiv , Prabhash Kumar 
Published: September 2018

e20628 Background: A repeat biopsy at the time of progression is important to evaluate the mechanism of resistance to tyrosine kinase inhibitors (TKIs) in EGFR mutation positive adenocarcinoma (ADC) of lung and dictates decisions for further therapy. Being an invasive procedure, a rebiopsy is not always possible and presents various hindrances. Methods: Between January 2012 and November 2016, EGFR mutation positive ADC of Lung treated with TKIs were evaluated for and offered a repeat biopsy at the time of progression on TKI. Feasibility of rebiopsy was done by a team of experienced interventional radiologists. Proportion of patients undergoing a rebiopsy, reason for inability to undergo a rebiopsy, histopathology findings including any small cell transformation and adequacy of tissue for further molecular testing were assessed. Results:154 patients were offered a repeat biopsy out of which 119 patients (77.3%) underwent a repeat biopsy. There was no evidence of malignancy in 17.6% (21/119) patients on the rebiopsy specimen and tumor was inadequate for molecular testing in 9 out of 98 patients (9.2%) in whom malignancy was detected on the repeat biopsy specimen. Small cell transformation was seen in 3.3% (4/119) patients who underwent a repeat biopsy. Amongst the 34 patients who could not undergo rebiopsy, patient unwillingness for the procedure was the most common reason, accounting for 47% cases (16/34) followed by a technically difficult biopsy as per judgement of the interventional radiology team in 32.3% (11/34). 5 out of 34 patients were not subjected to a rebiopsy a poor performance status and 3 patients were not subjected to rebiopsy as per treating clinician’s discretion. Thus, out of 154 patients, adequate tissue was not available for molecular testing in 41.5% patients who progressed on TKI due to various reason as elaborated above. Molecular testing is planned on the remaining biopsy specimens. Conclusions: Conventional invasive rebiopsy upon progression on TKIs fails to collect adequate tissue for molecular testing in almost 40% cases due to various reasons making liquid biopsy a very important tool in this setting.
Neutrophil lymphocyte ratio (NLR) as a predictive biomarker for PD-1/PD-L1 directed therapy in metastatic non-small cell lung cancer (NSCLC).
Authors: Bumma Naresh , Jeyakumar Ghayathri , Kim Seongho , Galasso Cathy , Thakur Manish K. , Gadgeel Shirish M. , Vaishampayan Ulka N. , Wozniak Antoinette J. 
Published: September 2018

e20633 Background: PD-1/PD-L1 directed therapy is approved in the second and first-line treatment of metastatic NSCLC. While PD-L1 expression can be predictive of outcomes with such therapy, there remains a need for additional biomarkers to guide patient (pt) selection. NLR is an easy to use biomarker that was predictive for clinical outcomes in the treatment of kidney cancer and melanoma. This study evaluated NLR as a predictor of response rate (RR), PFS and OS in metastatic NSCLC pts treated with PD-1/PD-L1 inhibitors as second line therapy. Methods: A retrospective chart review of NSCLC pts treated with PD-1/PD-L1 inhibitors was conducted. Data were collected on pt demographics, smoking status [<10 pack years (PY) and ≥10 PY], histology, NLR pre-therapy and NLR post 3 doses. Correlation with RR, PFS and OS was evaluated by univariate and multivariate analyses. Results: 58 pts with NSCLC were included in the analyses. Median age was 62.5 yrs (39-85) and 34(59%) were male. 36 (62%) were Caucasian, 16(28%) African American and 6(10%) Asian. 39 (63%) had adenocarcinoma histology, 23 (40%) patients smoked <10 PY and 35(60%) ≥10 PY. On Day 1, 33 (57 %) had NLR <4 and 28 (48%) had NLR <4 after cycle 3. 43 (74%) pts had disease control with 2 (3%) complete remissions, 22 (38%) partial responses. Pre-therapy NLR ≥4 was associated with shorter PFS (HR = 1.79 p=0.10) and shorter OS (HR =2.57; p=0.04). NLR≥4 post 3doses was associated with shorter PFS (HR= 2.14,p=0.04) and shorter OS (HR= 3.11; p=0.04). In multivariate analysis, heavy smoking (≥10 PPY) was associated with longer PFS; HR=0.50 (95% CI 0.25-1.01; p=0.05); but had no effect on OS with a HR 0.58(95%CI 0.21-1.56; p=0.28). Squamous histology appeared to have longer PFS HR=0.62 (95% CI 0.61-2.35: p =0.61), though not statistically significant. Conclusions: Pretherapy NLR ≥4 was found to be associated with shorter OS in NSCLC pts treated with PD-1/PD-L1 therapy. This suggests that NLR may be a predictive factor for benefit with PD1/PDL1 therapy. A larger sample study is warranted to validate this observation. [Table: see text]