bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence and clinical correlation of programmed cell death 1 ligand (PD-L1) expression in patients with resected non-small cell lung cancer (NSCLC): Results from the European Thoracic Oncology Platform (ETOP) Lungscape cohort.
Authors: Kerr Keith , Thunnissen Erik , Dafni Urania , Soltermann Alex , Finn Stephen P. , Bubendorf Lukas , Verbeken Eric , Biernat Wojciech , Warth Arne , Marchetti Antonio , Speel Ernst-Jan M. , Pokharel Saraswati , Quinn Anne Marie , Monkhorst Kim , Navarro Atilio , Madsen Line Bille , Polydoropoulou Varvara , Kammler Rosita , Peters Solange , Stahel Rolf A. ,   ETOP Lungscape Consortium
Published: September 2018

8516 Background: Conflicting data exists on the potential prognostic impact of PD-L1 expression in NSCLC. The Lungscape project, a fully annotated large biobank of resected stage I-III NSCLC, allows detailed analysis of this issue. Methods: Prevalence of PD-L1 positivity and its association with clinicopathological characteristics and patient outcome - Relapse-free Survival (RFS), Time-to-Relapse (TTR) and Overall Survival (OS) - was explored in the ETOP Lungscape cohort. PD-L1 expression was assessed on tissue microarrays (TMAs) using the DAKO 28-8 immunohistochemistry assay. Positivity cut-off points of ≥1%, 5% and 50% for neoplastic cell membrane staining were considered. Results: PD-L1 data were available for 2182 patients, from 15 ETOP centers, with median follow-up 4.8 years; 1191 patients still alive; median age 66 years; 64% male, 32/54/11% for current/former/never smokers; 49/29/22% for stages I/II/III; 51/42/4/3% adenocarcinomas (AC)/squamous cell (SCC) /large cell and sarcomatoid (LCS)/other. Median RFS/TTR/OS were 53/99/69 months (AC: 52/84/72, SCC: 54/not reached/64; and LSC 52/103/74). PD-L1 prevalence with 1% cut-off was, overall: 43%, 95% confidence interval (95%CI): 41-46; (AC: 42%, 95%CI: 39-46; SCC: 44%, 95%CI: 40-47; and LCS: 53%, 95%CI: 42-65), while for 5% threshold, prevalence was 34%, 95%CI: 32-36. PD-L1 1% positivity was a significant predictor only for AC: HRRFS: + vs - = 0.82; 95%CI: 0.69-0.97, HRTTR: + vs - = 0.83; 95%CI: 0.68-1.01, HROS: + vs -= 0.83; 95%CI: 0.69-1.01 (adjusted p = 0.024, 0.064, 0.063 respectively). This effect is found also for the 5% cut-off, and preserved in the overall model including all histologies. Using the 50% cut-off, PD-L1 positivity was detected in 17% of patients; 95%CI: 15-18, but was no longer a significant predictor of outcome, overall and by histology type. Conclusions: PD-L1 positivity (1% and 5% cut-offs) was present in more than one third of resected NSCLC and was associated with a better prognosis for AC patients.
Temporal trend in the use of surgery in the management of stage IIIa non-small cell lung cancer (NSCLC) between 2000-2013: A SEER analysis.
Authors: Iyer Veena , Hakim Hosam , Bagchi Arindam , Nai Qiang , Hamouda Danae , Barnett William , Skeel Roland T. 
Published: September 2018

8524 Background: The optimal treatment of patients with Stage IIIA NSCLC, a heterogeneous group comprised of T1-T4, N0-N2 disease, is controversial. Lack of clear data and guidelines allows several options for treatment, and hence there has been significant variability in clinical practice. The purpose of this study was to evaluate the nationwide trends in rates of surgery for Stage IIIA lung cancer diagnosed between 2000-2013. Methods: The study included patients with Stage IIIA NSCLC, 18 years and older diagnosed between 2000 and 2013. We used Z-tests in SEER*Stat to compare relative survival rates for patients diagnosed between 2000-2010. Results: Among the 27,697 patients with Stage IIIA NSCLC, 45% were females and median age was 67. 35% were treated with surgery. Multivariate analysis demonstrated that year of diagnosis, race, marital status, geographic region, tumor size, tumor grade, nodal status all were significantly associated with the use of surgery. Relative survival at 24 months (RS24) was 62% for patients who had surgery and 29% for patients without surgery (z = -47.3). The proportion of patients receiving surgery decreased from 55.6% in 2000 to 32.6% in 2010 and 29.7 in 2013 (p < 0.0001) while the relative survival at 24 months (RS24) from 2000 to 2010 rose from 34.7% to 43.2% (z = -4.89). The RS24 for patients who received surgery rose from 55.3% in 2000 to 77.6 % in 2010 (z = -3.58). Change in RS24 for patients who did not have surgery also improved from 19.6% to 31.2%. The median RS of the surgical cohort changed from 28 m to 44 m. Conclusions: Based upon reporting within the SEER database, the proportion of stage IIIA NSCLC patients undergoing surgery has decreased over the study time period. However, the relative survival rates have improved significantly for both the overall group and those having surgery, suggesting that significant strides have been made both in selecting the group of patients who would benefit from surgical resection and in the overall management of this group of patients.
Survival benefit of systemic chemotherapy given as adjuvant (ACT) after thoracic surgery for N0-1 non-small cell lung cancer (NSCLC) patients (pts) with synchronous brain metastasis (SBM).
Authors: Shin Sarah , Yendamuri Saikrishna S. , Groman Adrienne , Dy Grace K. 
Published: September 2018

8525 Background: Pts with solitary SBM and otherwise early-stage NSCLC demonstrate prolonged survival with surgical resection of both primary and metastatic disease. The role of “ACT” after thoracic surgery in this circumstance is not well-defined. We seek to determine the effect on overall survival(OS) of ACT after resection of primary tumor in pts with surgically resectable primary NSCLC and SBM. Methods: The National Cancer Database (NCDB) was queried to identify pts who underwent resection of NSCLC as the primary cancer (without other malignancies) from years 2010-2014 (n = 90,518). We then focused on pts who also were diagnosed with SBM (n = 807). Only patients with pathologically confirmed N stage 0 (n = 419) or 1 (n = 101) status were included in the final analysis. Patients who received platinum-based ACT within 3 months after surgery were considered to have received ACT. Associations between treatment groups were analyzed using the Chi-square test for categorical variables and Wilcoxon Rank Sum test for continuous variables. Univariate and multivariate proportional hazards modeling results were used to assess the effect of treatment and the confounding variables on OS. Relative prognosis was summarized using estimates and 95% confidence interval(CI) for the hazard ratio (HR). Unadjusted differences in OS between the treatments are shown using Kaplan-Meier methods. All analyses were performed using SAS version 9.4. Results: There is no imbalance in terms of gender, race, income, nodal status, histology between groups. Non-ACT pts were older (n = 181, median 64 vs 58 years in ACT group, p < 0.001). Age, nodal status, ACT, and histology were associated with OS in both univariate and multivariate analysis, with OS HR 0.51 (95% CI 0.39-0.66) in favor of ACT (n = 339). One- and 5-year survival in ACT group versus non-ACT group was 83% (95% CI 78%-87%) and 33% (25%-40%), versus 57%(95% CI 48%-65%) and 18% (95% CI 11%-26%), respectively. Conclusions: ACT after thoracic surgery for N0-1 NSCLC with SBM is associated with improved OS in this analysis.
Early experience with IBM Watson for Oncology (WFO) cognitive computing system for lung and colorectal cancer treatment.
Authors: Somashekhar S.P. , Sepúlveda Martín-J. , Norden Andrew D , Rauthan Amit , Arun Kumar , Patil Poonam , Ethadka Ramya Y , Kumar Rohit C 
Published: September 2018

8527 Background: IBM Watson for Oncology is an artificial intelligence cognitive computing system that provides confidence-ranked, evidence-based treatment recommendations for cancer. In the present study, we examine the level of agreement for lung and colorectal cancer therapy between the multidisciplinary tumour board from Manipal Comprehensive Cancer Centre in Bangalore, India, and Watson for Oncology. Methods: Watson for Oncology is a Memorial Sloan Kettering Cancer Center (New York, USA) trained cognitive computing system that uses natural language processing and machine learning to provide treatment recommendations. It processes structured and unstructured data from medical literature, treatment guidelines, medical records, imaging, lab and pathology reports, and the expertise of Memorial Sloan Kettering experts to formulate therapeutic recommendations. Treatment recommendations are provided in three categories: recommended, for consideration and not recommended. In this report we provide the results of the independent and blinded evaluation by the multidisciplinary tumour board and Watson for Oncology of 362 total cancer cases comprised of 112 lung, 126 colon and 124 rectal cancers seen at the Centre within the last three years. The recommendations of the two agents were compared for agreement and considered concordant when the tumour board recommendation was included in the recommended or for consideration categories of the treatment advisor. Results: Overall, treatment recommendations were concordant in 96.4% of lung, 81.0% of colon and 92.7% of rectal cancer cases. By tumour stage, treatment recommendations were concordant in 88.9% of localized and 97.9% of metastatic lung cancer, 85.5% of localized and 76.6% of metastatic colon cancer, and 96.8% of localized and 80.6% of metastatic rectal cancer. Conclusions: Treatment recommendations made by the Manipal multidisciplinary tumour board and Watson for Oncology were highly concordant in the cancers examined. This cognitive computing technology holds much promise in helping oncologists make information intensive, evidence based treatment decisions.
Comprehensive molecular and immune profiling of non-small cell lung cancer and matched distant metastases to suggest distinct molecular mechanisms underlying metastasis.
Authors: Lee Won-Chul , Gomez Daniel Richard , Zhang Jianhua , Jalali Ali , Roh Whijae , Reuben Alexandre , Lu Wei , Chow Chi-Wan , Wu Chia Chin , Fujimoto Junya , Antonoff Mara , Moran Cesar , Sulman Erik P. , Rao Ganesh , Swisher Stephen , Heymach John , Wistuba Ignacio Ivan , Futreal Andrew , Zhang Jianjun ,   Oligomets Study Team
Published: September 2018

8541 Background: Despite complete resection, many non-small cell lung cancer (NSCLC) patients still develop and succumb to distant metastases. Previous studies suggested distant metastasis may be due to genomic evolution and/or suppressed immune surveillance. However, the relationship between specific genomic alterations and immune surveillance has not been systemically studied. Methods: We performed whole exome sequencing, RNA-Seq, methylation microarray, immunohistochemistry using multiple immune markers, and T cell receptor sequencing on 7 pairs of NSCLC primary tumors and matched metastases including 6 metachronous brain and 1 synchronous liver metastases. Results: On average, 84% of all somatic mutations (54% to 97%) and all 28 canonical cancer gene mutations were shared between primary tumors and paired distant metastases. Metastases also resembled paired primary tumors closely in regard to somatic copy number aberration profiles, methylation profiles. Subclonal analysis showed almost identical clonal architectures in 4 of 7 pairs of primary tumor and metastasis comparable to the similarity observed between different regions within the same tumors. The other 3 pairs, however, displayed clear evidence of clonal evolution. We validated these findings in a published dataset consisting of 38 pairs of primary NSCLC tumors and matched distant metastases. The RNA-Seq data showed that 25 of the top 35 significantly down-regulated signaling pathways in metastases relative to primary tumors were related to immune activation, which was validated in an independent cohort of 41 primary NSCLC tumors and distant metastases using NanoString’s PanCancer Immune Profiling Panel. Conclusions: Our data suggest that molecular mechanisms underlying postsurgical distant metastasis may be variable among NSCLC patients. While genomic evolution may play a role in development of metastasis in some patients, distant metastasis may be early event during carcinogenesis without further genomic evolution in a substantial proportion of NSCLC patients. Furthermore, immune suppression may be a characteristic of cancer cells of metastatic capacity.
Detailed pathologic evaluation of low dose CT (LDCT) detected stage I/0 lung adenocarcinomas (ADCA).
Authors: Burks Eric , Sands Jacob , Sullivan Travis B. , Rieger-Christ Kimberly M. 
Published: September 2018

8543 Background: Although LDCT lung screening improves survival, some worry that indolent BAC-like ADCA may be over-detected/treated. Comprehensive histologic subtyping has recently been adopted to improve grading and thus risk stratification in lung ADCA. We report a detailed pathologic comparison of stage I/0 lung ADCAs detected by LDCT screening vs. incidentally discovered ADCAs stratified by NCCN risk criteria. Methods: We performed comprehensive histologic subtyping on 35 consecutive stage I/0 LDCT screen detected ADCAs in patients meeting NCCN group 1/2 high risk (HR) criteria and compared to incidentally detected stage I/0 ADCAs meeting HR (n = 41) or low-risk (LR, n = 28) criteria. Results: Screen detected and incidentally detected ADCAs from HR groups show an equally low-rate of indolent, non-invasive/minimally invasive ADCAs (9%) compared to LR patients (36%). Aggressive solid predominant ADCAs were equally more frequent in HR patients from screen and incidentally detected patients (19%) compared to LR patients (6%). The rate of angiolymphatic invasion (59%) and air space invasion (32-34%) were similarly elevated in HR screen and incidental patients compared to LR patients (39% & 17% respectively). A collection of lepidic predominant (BAC-like) ADCAs associated with aggressive non-predominant cribriform and/or solid patterns, elevated mitotic rates, and high proportion of lymphatic invasion were uniquely observed in the screen-detected group (12%). Subgroup analysis of screen detected NCCN group 1 vs. 2 shows group 2 tumors exhibit histologic features which are at least as aggressive as group 1 tumors, albeit at smaller invasive sizes (1.2 cm vs. 1.5 cm) and lower stage (IA 75% vs. 61%). Conclusions: This is the first detailed pathologic comparison of LDCT screen detected vs incidentally discovered stage I/0 ADCA. Tumors from HR patients are pathologically more aggressive than LR tumors. Not all BAC-like tumors in LDCT screen detected patients should be presumed indolent given that approximately half of these bear histologic features of aggressive ADCAs while still in a lepidic predominant phase. NCCN group 2 tumors are similar to group 1 and should be further studied.
Phase Ib study of tepotinib in EGFR-mutant/c-Met-positive NSCLC: Final data and long-term responders.
Authors: Wu Yi-Long , Soo Ross A. , Kim Dong-Wan , Yang James Chih-Hsin , Scheele Jürgen , Chen Wenfeng , Becker Andreas , Park Keunchil 
Published: September 2018

8547 Background: Patients (pts) with NSCLC that is initially responsive to EGFR tyrosine kinase inhibitors (EGFR TKI) typically develop resistance, often associated with aberrant c-Met activity. Dual inhibition of EGFR and c-Met is therefore a rational option to treat c-Met+ EGFR TKI-resistant NSCLC. Tepotinib is a highly selective c-Met inhibitor with good tolerability and promising activity against solid tumors. We report final data from a phase Ib trial of tepotinib + gefitinib in pts with c-Met+/EGFR-mutant NSCLC conducted in Asia. Methods: Eligible pts were adults with locally advanced/metastatic NSCLC and ECOG PS 0–1. Tumors had to express EGFR with an activating mutation be resistant to EGFR TKI therapy and be c-Met+ by IHC. Pts received tepotinib 300 or 500 mg QD combined with gefitinib 250 mg QD (T300G250 or T500G250). The primary objective was to determine the recommended phase II dose (RP2D) of tepotinib in combination with gefitinib; secondary objectives included pharmacokinetics (PK), safety, and antitumor activity. Results: 18 pts were enrolled (median age 65 [41–78]; 8 male); 6 received T300G250, 12 T500G250. No dose-limiting toxicities were observed, and tepotinib 500 mg QD was confirmed as the RP2D. 17 pts experienced treatment-related treatment-emergent adverse events (TRTEAEs), mostly grade ≤2 and most commonly diarrhea (12), rash (8), and amylase increase (6). Grade ≥3 TRTEAEs were increased amylase (n = 4), increased lipase (3), neutropenia (1), and hyperglycemia (1). The best overall response was partial response in 6 pts; 4/7 pts with IHC 3+ tumors responded (all treated with T500G250) vs 2/11 with IHC 2+ tumors. Response durations of pts with PR were 4.2–12.5 months. 4/18 pts (IHC 2+, n = 3) had stable disease. 8 pts experienced progression free survival > 5 months, 3 pts > 10 months. PK were as expected from previous studies. Conclusions: Tepotinib in combination with gefitinib was well tolerated. The RP2D of tepotinib for use in combination with gefitinib in NSCLC is 500 mg QD. T500G250 showed signs of activity against c-Met+ tumors. A phase II trial is randomizing ≈156 pts with c-Met+/T790M– tumors who have failed first-line EFGR TKI 2:1 to tepotinib + gefitinib or pemetrexed + cisplatin/carboplatin. Clinical trial information: NCT02864992.
Patterns of metastases in malignant pleural mesothelioma in the modern era: Redefining the spread of an old disease.
Authors: Collins Dearbhaile Catherine , Constantinidou Anastasia , Sundar Raghav , Chenard-Poirier Maxime , Yap Timothy Anthony , Banerji Udai , De Bono Johann S. , Lopez Juanita Suzanne , Tunariu Nina 
Published: September 2018

8556 Background: Malignant pleural mesothelioma (MPM) has been historically documented as a locally infiltrative disease in large series from the early 1980s. With the changing landscape of cancer diagnosis and treatment, increased areas of unusual metastases have been published as case reports. With no standard second-line therapies for MPM, referral to early phase trial units is common. We report the metastatic patterns of a large cohort of MPM patients treated at the Royal Marsden Drug Development Unit (DDU). Methods: Clinical data was gathered for MPM patients referred to the DDU from 1992 to 2016. Radiographic details were collected from CT, bone scan and FDG PET imaging. Prior treatment, response, somatic mutations, clinical trial and survival data was obtained from medical records. Results: From the database, 165 evaluable patients with MPM were identified. Median age at diagnosis was 64 years (range 37–90) and 76% were male. Epithelioid MPM comprised 81% and 65% were right sided. Bone metastases were reported in 20%, with the majority lytic in nature ( Table). Peritoneal and omental disease was evident in 24% with ascites in 16%. In 11% of cases lung metastases presented as diffuse miliary-type pattern. Visceral metastases (15%) were predominantly liver (78%), but also occurred in adrenals, spleen and kidneys. Symptomatic brain metastases were recorded in 3%. Median overall survival was 24.2 months (95% CI: 20.8 - 29.2). Conclusions: This large study documents the metastatic patterns of advanced MPM in the 21st century and highlights an increased frequency of traditionally unexpected sites of metastases. Higher than expected incidence of lytic bone metastases (20%) suggests consideration of bone imaging in advanced MPM clinical workflow and trial protocols. [Table: see text]
Biomarkers of pembrolizumab (P) activity in mesothelioma (MM): Results from a phase II trial.
Authors: Kindler Hedy L. , Karrison Theodore G. , Rose Buerkley , Tan Y-H Carol , Khattri Arun , Acharya Rajesh , Straus Christopher M. , Seiwert Tanguy Y. 
Published: September 2018

8557 Background: PD-L1 expression and the Interferon-Gamma gene expression profile (IFN-G GEP) are predictive of response to checkpoint blockade in several solid tumors. Relevant biomarkers in mm pts treated with these agents have not been determined; these were evaluated in a phase 2 trial of P in mm (NCT02399371). Methods: Eligible pts had histologically confirmed MM, PS 0-1, disease progression on 1-2 prior regimens. P 200 mg was given Q21 days. Part A (N = 35) determined the response rate (RR) of P in PD-L1 unselected mm pts and assessed an optimal PD-L1 threshold (22C3 IHC assay). If ≥3 responses, the study proceeded to Part B (N = 30), using a biomarker enrichment strategy if a threshold was found. Nanostring nCounter was used to assess IFN-G GEP (6 gene). Results: 35 pts enrolled in Part A 5/15-2/16; 1 withdrew. Median age 66 (range 26-85); PS 0: 62%; male: 82%; epithelial/sarcomatoid/biphasic/NOS: 74%/21%/3%/3%; pleural/peritoneal: 85%/15%; 2nd-line: 59%. Partial response (PR): 7 (21%), stable disease (SD): 20 (59%). Median response duration: not reached. Median progression-free survival (PFS): 6.2 months (95% CI: 3.2, 8.2). Median overall survival: 11.9 months (95% CI: 6.4, --). Toxicity ≥ grade 3: adrenal insufficiency, fatigue, pneumonitis 6%; colitis, confusion, hepatitis, hyponatremia, neutropenia, rash 3%. PD-L1 expression by tumor proportion score (N = 32): none (53%); 1-49%: (22%); ≥50%: (25%). PD-L1 IHC (ROC area 0.63; 95% CI: 0.37, 0.89), CD274 mRNA expression, and IFN-G GEP did not correlate statistically with response. Responses occurred in GEP low, non-inflamed tumors, and in PD-L1- tumors. RR was numerically higher in PD-L1+ (27%) than in PD-L1- pts (12%); there was a trend towards longer PFS and OS in PD-L1+ pts. Conclusions: P has clinically meaningful single-agent activity in PD-L1 unselected, previously treated mm pts, achieving a 21% RR and a disease control rate of 80%. Biomarkers established in other cancers, such as PD-L1 IHC and IFN-G GEP, may not be as useful in MM. Novel biomarkers including MM-specific gene signatures may be necessary and are being evaluated. Part B of the study is ongoing with no PD-L1 pre-selection (19/30 pts enrolled), and will be used as a biomarker validation cohort. Funded by a MARF grant. Clinical trial information: NCT02399371.