bluuebunny/crossref_metadata_2025_split huggingface dataset:
The tumor microenvironment in EGFR-driven loco-regional lung adenocarcinoma can predict higher risk of recurrence.
Authors: Khalil Maya , Elkhanany Ahmed , Yang Yuanquan , Glenn Sean , Papanicolau-Sengos Antonios , Morrison Carl , Dy Grace K. 
Published: March 2020

8521 Background: The role of EGFR tyrosine kinase inhibitors (TKIs) as adjuvant therapy in EGFR-mutated NSCLC is still controversial. Identifying biomarkers associated with increased risk of recurrence may help stratify pts & guide adjuvant therapy. We hypothesized that tumor immune microenvironment (TME) alterations could predict disease-free survival (DFS) in these pts. Methods: The Cancer Genome Atlas (TCGA) lung Adenocarcinoma (LUAD) data at Genomic Data Common (GDC) was accessed for pt phenotype, updated outcome & normalized gene expression profile (RNA seq). Immune landscape data was obtained from PANCAN. We chose to focus on 54 key TME genes, identified from a commercially available immune report card from OmniSeq (Inc.). Pt groups were divided via K-mean clustering. Group comparison was done via Likelihood Ratio (LR, categorical), Mann Whitney (continuous), log-rank (survival) & Cox regression (outcome). Bonferroni correction was used to correct for multiple comparisons. Results: 877 pts with LUAD were identified, 32 of whom had EGFR mutations and were at stages I to III. The mutations were mostly in the TK domain, involving exons 18 (12%), 19 (27%), 20 (6%), & 21 (33%). Only 3% harbored the T790M mutation. None of the pts received adjuvant TKI. Analysis of the impact of individual genes on DFS yielded a group of 8 genes whose high expression was associated with improved DFS: IL10 (HR 0.58, p 0.029), BTLA (HR 0.66, p 0.07), CD8A (HR 0.6252, p 0.099), CD39 (HR 0.454, p 0.037), CCR2 (HR 0.729, p 0.039), CSF1R (HR 0.70, p 0.087), ICOS (HR 0.66, p 0.062), & CD4 (HR 0.67, p 0.059). K-mean clustering of the pts using these genes demonstrated 2 groups with distinct immune profiles. Group 1 was characterized by higher leukocyte and stromal fractions, lymphocyte infiltration score, macrophage regulation, TGF-ß response, & T cell richness with less proliferation, pointing towards a more “inflamed” phenotype. Significant difference between the two groups in the immune subtypes was found (LR 10, p = 0.039). 90% of pts in the inflamed group had tumors with IFN-γ dominant, inflammatory, and TGF-ß dominant subtypes, while 45% of the “non-inflamed” group had lymphocyte depleted & wound healing signatures. DFS was significantly longer in the inflamed group (median DFS 1480 vs 772 days, p = 0.002). Conclusions: In pts with resected EGFR-mutated LUAD, an inflamed TME is associated with prolonged DFS. Identifying these pts may help select those who would benefit from adjuvant therapy.
Updated survival date of phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy for patients with locally advanced non-small cell lung cancer.
Authors: Horiike Atsushi , Kawano Yuko , Sasaki Tomonari , Yamaguchi Hiroyuki , Hirano Katsuya , Satouchi Miyako , Hosokawa Shinobu , Morinaga Ryotaro , Komiya Kazutoshi , Inonue Koji , Fujita Yuka , Toyozawa Ryo , Kimura Tomoki , Takahashi Kosuke , Nishikawa Kazuo , Kishimoto Junji , Nakanishi Yoichi , Okamoto Isamu 
Published: March 2020

8529 Background: Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non–small cell lung cancer (NSCLC). Methods: Patients between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. In the phase II part of the study, patients received weekly nab-paclitaxel at 50 mg/m2 together with weekly carboplatin at an area under the curve (AUC) of 2 mg mL–1 min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. The primary end point of the phase II part of the study was progression-free survival (PFS). Results: Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0 to 49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1% to 76.8 %). The median PFS was 11.8 months (60% CI, 10.6 to 16.8 months; 95% CI, 8.2 to 21.0 months). The overall response rate was 76.8% (95% CI, 64.2% to 85.9%), and the disease control rate was 94.6% (95% CI, 85.4% to 98.2%). Subgroup analysis according to histology or age revealed no significant differences in median PFS or OS. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). Pneumonitis of grade 3 was observed in two patients during the study period. No treatment-related deaths occurred. Conclusions: Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m2 and carboplatin at an AUC of 2 mg mL–1 min in patients with locally advanced NSCLC. Clinical trial information: UMIN000012719.
Efficacy and safety of neoadjuvant PD-1 blockade with sintilimab in resectable squamous non-small cell lung cancer (sqNSCLC).
Authors: Li Ning , Ying Jianming , Tao Xiuli , Zhang Fan , Zhao Ziran , Ling Yun , Gao Yushun , Zhao Jun , Xue Qi , Mao Yousheng , Lei Wendong , Wu Ning , Wang Shuhang , Duan Jianchun , Gao Yibo , Wang Zhijie , Sun Nan , Wang Jie , Gao Shugeng , He Jie 
Published: March 2020

8531 Background: NSCLC patients who have potentially resectable disease often subsequently relapse after surgery. New therapy that prevents relapse after surgery is desperately needed. In this study, we tested the efficacy and safety of neoadjuvant sintilimab, an anti-PD-1 antibody, for patients with resectable sqNSCLC in China. Methods: All patients had treatment-naïve resectable sqNSCLC (stage IB-IIIA) that was confirmed by histopathology. Patients received two cycles of sintilimab (200 mg IV) on Day 1 and 22. Surgery was performed between Day 29-43. An enhanced PET/CT was obtained at baseline and seven days prior to surgery. Preliminary analysis of safety profile and efficacy was planned after at least 20 patients had received operation. Results: As of Jan. 28, 2019, 22 patients (20 males and 2 females) with sqNSCLC received two doses of sintilimab followed by radical resection. The median age was 61.5 yr (range, 48 to 70). Six (27.3%) and four (18.2%) patients experienced neoadjuvant treatment emergent adverse events (TEAEs) and neoadjuvant treatment-related AEs (TRAEs), respectively. Most of the TEAEs and TRAEs were grade 1 or 2. Three patients achieved radiological partial response: an ORR of 13.6% based on RECIST 1.1. Ten patients (45.5%) achieved a major pathologic response (MPR, ≤10% viable tumor cells), including four (18.2%) had complete pathologic response (no viable tumor cell). There was a direct correlation between pathological response and decrease in the standardized uptake values (SUV) in the primary tumor. Among nine patients with > 30% decrease of SUV, eight had MPR, compared with no MRP response in the 11 patients with ≤30% decrease of SUV. Conclusions: Neoadjuvant sintilimab for sqNSCLC patients was tolerable and the 45.5% MRP rate is encouraging. A decrease in SUV may be predictive of pathologic response after PD-1 therapy in sqNSCLC. Clinical trial information: ChiCTR-OIC-17013726.
Association of BAFFR expression in CAFs with overall survival and response to platinum-based chemotherapy in NSCLC.
Authors: Dimtrakopoulos Fotinos-Ioannis D. , Kottorou Anastasia E , Antonacopoulou Anna G , Nikolakopoulos Achilleas , Panagopoulos Nikolaos , Kalofonou Melpomeni , Dougenis Dimitrios , Koutras Angelos , Makatsoris Thomas , Tzelepi Vasiliki , Kalofonos Haralabos 
Published: March 2020

8537 Background: Β-cell activating factor receptor (BAFFR) is a surface receptor, which leads to activation of the Nuclear Factor-kappaB (NF-κB) alternative pathway, a pathway with an important role in non-small cell lung cancer (NSCLC). In addition, cancer associated fibroblasts (CAFs) are major players of the tumor microenvironment promoting NSCLC. The aim of this study was to assess the possible associations of BAFFR expression in CAFs with response to first-line chemotherapy doublet and clinical outcome of NSCLC patients. Methods: Immunohistochemical analysis of BAFFR expression on CAFs was performed on tumor and tumor-adjacent formalin fixed and paraffin embedded tissue samples from 124 operated patients with NSCLC. Patients were under follow-up for at least 60 months, while response to chemotherapy was evaluated in patients who relapsed during this period. Results: BAFFR expression, which was noted exclusively in the cytoplasm of CAFs, was associated with OS only in patients with no infiltration of regional lymph nodes. Higher expression levels of BAFFR in CAFs were related to worse 2-, 3- and 5-year survival (P = 0.015, P = 0.027 and P = 0.040, respectively). This finding persisted after multivariate analysis with age, gender, histological subtype, histological differentiation and disease stage as coefficients (P = 0.009; HR, 2.734; 95% CI, 1.283-5.828). In addition, response to first line chemotherapy was associated with BAFFR expression in CAFs (P = 0.025). Patients who progressed had lower BAFFR levels. Furthermore, BAFFR expression in CAFs was associated with patients’ age. In particular, older patients had higher expression of BAFFR compared to patients younger than 55 years (P = 0.010). Additionally, carcinomas with better differentiation had lower expression of BAFFR in CAFs (P = 0.005). Finally, BAFFR expression in CAFs was related to development of metastatic disease (P = 0.033) and particularly in liver (P = 0,017) and in bones (P = 0.003). Conclusions: The present findings suggest that the expression of BAFFR in CAFs may be a useful biomarker with prognostic and predictive value, representing possibly an unknown biological relation, which merits further investigation.
Assessment of PD-L1 expression and oncogenic gene status in patients with small-cell lung cancer: Immuno-oncology biomarker study in LC-SCRUM-Japan.
Authors: Oizumi Satoshi , Yoh Kiyotaka , Matsumoto Shingo , Miyamoto Shingo , Furuya Naoki , Sasada Shinji , Okamoto Norio , Hayashi Yuichiro , Tsuta Koji , Motoi Noriko , Ishii Genichiro , Goto Koichi 
Published: March 2020

8558 Background: The clinical impact of PD-L1 expression and oncogenic gene status in patients with small cell lung cancer (SCLC) is not well characterized. We initiated this immuno-oncology biomarker study as part of nationwide genomic screening by LC-SCRUM-Japan (LC-SCRUM-IBIS). Methods: Tumor samples from lung cancer patients enrolled in LC-SCRUM-IBIS were primarily subjected to targeted next-generation sequencing (NGS) with Oncomine™ Comprehensive Assay. The PD-L1 expression was also analyzed by 4 immunohistochemistry (IHC) assays for 22C3, 28-8, SP263 and SP142. At this analysis, 22C3, 28-8, and SP263 were assessed in tumor cells (TC) as positive in > 1%, and SP142 in both TC and tumor-infiltrating immune cells (IC) as positive in > TC1/IC1, as previously reported. The association of PD-L1 expression, oncogenic gene status and clinical outcome was investigated in SCLC patients. Results: Between Feb 2017 and May 2018, 1017 lung cancer patients were enrolled in LC-SCRUM-IBIS. Among them, 933 patients had adequate tumor samples including 101 SCLC and 832 non-small cell lung cancer. Of 101 SCLC patients, the results of PD-L1 expression by 4 IHC assays were 18% in 22C3, 17% in 28-8, 11% in SP263 and 8% in SP142, respectively. Targeted NGS showed that 8 patients had at least one targetable oncogenic alterations, including 3 PIK3CA and 1 KRAS as mutations and 3 PTEN and 1 TSC2 as inactivating mutations. PD-L1 expression by 22C3 was associated with good performance status (P = 0.05) and the presence of oncogenic alterations (P = 0.004). PD-L1 status was not associated with response to cytotoxic chemotherapy and progression-free survival and overall survival in first-line treatment of SCLC patients. Conclusions: The frequency of PD-L1 expression in SCLC patients was relatively lower compared with that reported in other solid tumors. PD-L1 status by TC in 22C3 appears to be not correlated with clinical outcomes for cytotoxic chemotherapy of SCLC patients. Further investigation is needed to explore a predictive biomarker for immune checkpoint inhibitors. Updated results will be presented at the meeting.
BIOLUMA: A phase II trial of nivolumab in combination with ipilimumab to evaluate efficacy and safety in lung cancer and to evaluate biomarkers predictive for response—Preliminary results from the SCLC cohort.
Authors: Fischer Rieke Nila , George Julie , Scheel Andreas H. , Schloesser Hans Anton , Vehreschild Maria , Brossart Peter , Engel-Riedel Walburga , Griesinger Frank , Grohé Christian , Kambartel Karl-Otto , Kern Jens , Hermes Barbara , Nachtkamp Kathrin , Panse Jens Peter , Sebastian Martin , Lehmann Markus , Wiewrodt Rainer Gerhard , Büttner Reinhard , Thomas Roman K. , Wolf Juergen 
Published: March 2020

8563 Background: Patient selection, dosing regimens and resistance mechanisms for immune checkpoint inhibitor combination therapy remain unmet medical needs in lung cancer. We present interim data from the small-cell lung cancer (SCLC) cohort of the ongoing BIOLUMA trial which evaluates efficacy and safety of nivolumab and ipilimumab in lung cancer with a broad translational program to identify potential biomarkers predictive of response and/or resistance including whole exome sequencing (WES) of serial biopsies, functional analysis of peripheral T-cells and gut microbiome analyses. Methods: BIOLUMA is an investigator initiated, multicentre non-randomised phase II trial in 2nd line patients with SCLC. The initial all-comer SCLC cohort was recently amended for inclusion of patients with high tumor mutation burden (TMB) only. Patients are pre-screened for TMB by WES at the time of first diagnosis. After progression on platinum-based therapy, 4 cycles of nivolumab 1 mg/kg q3w in combination with ipilimumab 3 mg/kg q3w and subsequent nivolumab 240 mg flat dose as monotherapy are given. Primary endpoint is overall response rate (ORR) of the upfront combination therapy. Analysis of sequential tumor biopsies, blood and gut microbiome is performed at different timepoints. Results: The SCLC cohort was amended to include TMB high patients only, after two treatment-related deaths had occurred and emerging data indicated treatment benefit depends on high TMB status for the combination therapy. Both patients with treatment-related death had a CT-scan documented partial response (not confirmed according to RECIST due to death). One each died of pneumonitis and encephalitis. From the all-comer cohort, efficacy data are available for 18 patients. ORR was 38.8% with 7 partial and no complete responses. Stable disease occurred in 16.7% (n = 3) resulting in a DCR of 55.5%. TMB pre-screening for the amended cohort is currently ongoing. Conclusions: In the SCLC cohort, upfront combination therapy of nivolumab and ipilimumab shows remarkable ORR but is accompanied by high toxicity rates. In order to ensure a reasonable balance of risks and treatment benefit, only TMB high patients are included after an amendment of the cohort to improve the risk/benefit ratio. Clinical trial information: NCT03083691.
Anti-EGFR target therapy in advanced thymic epithelial tumors.
Authors: Giuliano Mario , Ottaviano Margaret , Tortora Marianna , Gallinoro Roberta , Marino Mirella , Pizzuti Angela , Arundine Dario , Picozzi Fernanda , Di Lauro Vincenzo , Riccio Vittorio , De Placido Sabino , Palmieri Giovannella 
Published: March 2020

8567 Background: Thymic epithelial tumors (TETs), show a high rate of EGFR immunohistochemistry (IHC) positivity, however, the prognostic and predictive role of EGFR has not yet been well defined, and contradictory data have emerged regarding the delivering of anti-EGFR monoclonal antibodies in TETs. The outcomes of the largest series of thymoma patients treated with cetuximab, and its hypothetic immune-modulatory role, are here described. Methods: Seven patients with diagnosis of pre-treated advanced thymoma and score positivity 2+ and 3+ at EGFR-IHC, were treated with cetuximab as off-label modality, with a dose of 400 mg/m2 in the first cycle and 250 mg/m2 in the following cycles every 7 days, until disease progression, unacceptable toxicity, withdrawal of consent. Primary endpoint was Overall Response Rate ORR, assessed radiologically. Secondary endpoints were progression Free Survival (PFS), safety, and relationship between time to cetuximab progression (TTPc) and time to previous treatment progression (TTP1). During treatment with cetuximab lymphocyte subpopulations have been carefully monitored in 4 patients affected by both thymoma and Good syndrome (GS) defined as B-cell lymphocyte counts (CD19+) <100 cells/mm3 and/or Immunoglobulin G (IgG) levels <8 g/L. Results: With a median response duration of 17 months, a partial response was achieved in five patients (ORR=71%). Statistically significant correlation was found between disease response and EGFR-IHC score 2+ vs 3+ (P, .008), which statistically correlated also with the mPFS of 14 months (95% CI, 0.0-34.5). No grade 3 or 4 adverse events were registered. TTPc was longer than TTP1 in 6/7 patients (86%), with a TTPc / TTP1 ratio equal to 2.12. During cetuximab treatment, in the longest responder patient affected also by GS, a progressive increase of IgG level and of CD4/CD8 ratio has been registered as well as an increase of both CD19+lymphocytes and CD16+ 56+ lymphocytes has been detected in all the included patients with GS. Conclusions: Despite of the small number of patients and the off-label treatment modality, the data presented are worthy of confirmation in validated prospective studies in selected population with hyper-expression of EGFR. Further studies are also needed for deeply investigate the immunomodulatory role of cetuximab which seemed to temporarily revert sever immunodeficiency in our population.
The risk of second primary malignancy in patients with localized thymoma: A U.S. population-based study.
Authors: Uprety Dipesh , Arjyal Lubina , Narayana Swapna , Polewski Peter James , Bista Amir , Vallatharasu Yazhini , Lashari Bilal Haider , Khanal Amit 
Published: March 2020

8568 Background: Thymoma is a rare neoplasm of anterior mediastinum. Patients often have an indolent disease. The prognosis of limited stage disease is excellent with a 10-year survival rate of 70 to 80%. Data regarding the risk of second primary malignancy in thymoma survivors are limited in recent years. In this study, we aimed to determine the risk of second primary malignancies (SPMs) among patients with limited stage thymoma. Methods: We utilized the Surveillance, Epidemiology and End Results (SEER)-13 registry to identify adult patients (≥ 18 years) with limited stage thymoma. We calculated the risk of SPM, developing ≥ 6 months after an index thymoma diagnosis, using Multiple Primary Standardized Incidence Ratio and an Absolute Excess Risk (AER) between 2004 and 2010. Statistical significance was defined as p < 0.05. Results: The database identified a cohort of 1,544 patients with limited stage thymoma with a median follow-up duration of 107 months (11-281 months). A total of 176 (11.39%) patients developed SPMs with a median latency of 62.5 months (range 6-272 months). Median age at diagnosis of SPM was 69 years (range 25- 96 years). Overall, SPM occurred at an observed to expected (O/E) ratio of 1.53 (95% CI 1.32-1.76), p < 0.001 with an AER of 60.52 per 10,000 patient-years at risk. A significantly increased risk was noted for cancer of lung and bronchus (O/E 1.77, 95% CI 1.21-2.52, p = 0.004; AER 12.17/10,000), skin excluding basal and squamous (O/E 2.09, 95% CI 1.04-3.75, p = 0.03; AER 5.17/10,000), urinary bladder (O/E 2.14, 95% CI 1.17-3.6, p = 0.014; AER 6.72/10,000), thyroid (O/E 3.48, 95% CI 1.4-7.17,p = 0.009; AER 4.49/10,000), and leukemia (O/E 3.26, 95% CI 1.63-5.83, p = 0.001; AER 6.86/10,000), including acute lymphocytic leukemia (O/E 16.09, CI: 1.95-58.11; AER 1.69/10,000), acute myeloid leukemia (O/E 3.83, CI: 1.04-9.8; AER 2.66/10,000) and other acute leukemia (O/E 29.45, CI: 3.57-106.39; AER 1.74/10,000). The risk was not significant for lymphoma (Hodgkin and non-Hodgkin), chronic leukemia, oropharyngeal, digestive tract and hepatobiliary cancer as SPM. Conclusions: The risk for SPMs is significantly increased in patient with thymoma compared to general population. Given the long-term risk of SPM, patient should be followed closely with judicious use of age-appropriate cancer screening.
ECOG-ACRIN 5508: Pemetrexed, bevacizumab or the combination as maintenance therapy for advanced non-squamous NSCLC.
Authors: Ramalingam Suresh S. , Dahlberg Suzanne Eleanor , Belani Chandra Prakash , Saltzman Joel N. , Nambudiri Gopakumar S. , McCann John , Winegarden Jerome D. , Kassem Mohammed Azher , Mohamed Mohamed K. , Rothman Jan M. , Lyss Alan P. , Horn Leora , Stinchcombe Tom , Schiller Joan H. ,   ECOG-ACRIN Cancer Research Group
Published: March 2020

9002 Background: Maintenance therapy is a standard approach for advanced non-squamous NSCLC. Pemetrexed or bevacizumab are considered evidence-based options. The combination of bevacizumab and pemetrexed has been documented to improve progression-free survival (PFS). We conducted a phase 3 study to determine the optimal maintenance therapy for advanced NSCLC. Methods: Patients (pts) with advanced non-squamous NSCLC, no prior systemic therapy, and ECOG performance status 0/1 were treated with carboplatin (AUC = 6), paclitaxel (200 mg/m2) and bevacizumab (15 mg/Kg) every 3 weeks for up to 4 cycles (step 1). Patients with CR/PR/SD after 4 cycles were then randomized 1:1:1 to maintenance therapy with bevacizumab (15 mg/Kg), pemetrexed (500 mg/m2) or the combination of the two agents every 3 weeks until disease progression (step 2). The primary endpoint was overall survival (OS), defined as the time from randomization to death from any cause and censoring defined at the last date of followup. 1495 pts provided 81% power to detect a hazard ratio of 0.75 while controlling the 2-sided type I error at 0.025 for each comparison, assuming approximately 60% of those patients would be randomized. Results: We enrolled 1516 pts to step 1 (male 52%; ECOG PS 1 62%; adenocarcinoma 90%); After induction therapy, 874 (57%) pts were randomized to step 2 (median age 64 yrs; male 49%; ECOG PS 1 55%). Baseline characteristics were balanced across all three groups. The median follow-up in maintenance is 50.6 months. Conclusions: Single agent bevacizumab or pemetrexed is the optimal maintenance therapy for advanced non-squamous NSCLC. The combination of bevacizumab and pemetrexed cannot be recommended due to the lack of survival benefit in this definitive study. (Drs. Ramalingam, Dahlberg and Belani contributed equally to this work). Supported by the NCI: CA180820, CA180794,CA180799, CA180821, CA180838, CA180844, CA180847, CA180853, CA180857, CA180864, CA180867, CA180868, CA180870, CA180882, CA189830, CA189859, CA189863, CA189971. Clinical trial information: NCT01107626. [Table: see text]