bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep-learning analysis of CT imaging biomarker for PD-L1 expression to predict heterogeneous response to immune checkpoint inhibitors in non-small cell lung carcinoma.
Authors: Aum Jaehong , Park Sehhoon , Jeon Soyoung , Lim Eunji , Yoo Hyunsuk , Kim Ki Hwan , Paeng Kyunghyun , Ock Chan-Young , Lee Se-Hoon , Lee Ho Yun 
Published: May 2020

e21529 Background: Inter-tumoral genomic heterogeneity cause various immune status in tumor microenvironment, which may lead to indiscriminate response to immune checkpoint inhibitor (ICI) in patients with multiple lesions. Therefore, PD-L1 status from practically approachable, single lesion would not be always representative for immune status of whole metastatic lesions of a patient. To solve inter-tumoral heterogeneity issue before biopsy in clinic, we developed a deep-learning based CT biomarker for predicting PD-L1 status, then explored if the algorithm would also predict ICI response of multiple lesions in non-small cell lung carcinoma (NSCLC). Methods: Deep learning-based image analyzer was trained with CT images of NSCLC in Samsung Medical Center (SMC) (N = 104). Taking 3D patch of a lesion located by radiologists, 3D convolutional neural network was trained to predict PD-L1 (22C3 immunohistochemistry) tumor proportion score of each lung or lymph node lesion. The prediction model was validated using publicly available dataset (NSCLC Radiogenomics, N = 115). Finally, we applied the model to baseline CT who had multiple lesions (≥ 2) and also received ICI (SMC validation, N = 170). Tumor response was assessed based on RECIST 1.1, and discordant response was defined by best response of each lesion outside -10% ~ +10%. Results: Predicted PD-L1 score was positively correlated with real PD-L1 expression in NSCLC Radiogenomics (Pearson = 0.198, P= 0.0339). In SMC validation cohort, predicted PD-L1 score of each lesion was negatively correlated with ICI response of corresponding lesion (Pearson = -0.0941, P= 0.0325). Interestingly, 35 out of 170 (20.6%) patients showing discordant ICI response among lesions had worse progression free survival (PFS) (median PFS: 2.1m, 1.6m, 2.5m, and 18.7m in discordant response, concordant progress, stable, and regress, respectively, P< 0.001). Patients with discordant response had significantly wide-ranged predicted PD-L1 score compared with others (median range: 0.273 versus 0.185, P= 0.0079). Moreover, patient-level median of predicted PD-L1 scores of lesions was significantly associated with prolonged PFS (hazard ratio 0.69, P= 0.0401) and overall survival (hazard ratio 0.65, P= 0.0431). Conclusions: Deep-learning based imaging biomarker accurately predicts PD-L1 status of each metastasis, as well as independent ICI response reflecting inter-tumoral heterogeneity. This algorithm would guide which lesion would be representative in clinic.
Characterization of heterogeneity in three lung cancer patients with multiple nodules by whole exome sequencing.
Authors: Liu Dongcheng , Li Shixuan , Wang Jiaqing , Sun Xuefeng , Li Guofeng , Peng Bin , Ding Peikun , Cheng Zhiqiang , Zou Chang , Wang Guangsuo 
Published: May 2020

e21530 Background: Tumor heterogeneity is an important characteristic of malignant tumors that reflects the high complexity and diversity in the process of evolution. It can lead to differences in tumor growth rate, invasion, metastasis, drug sensitivity and prognosis. At present, there exist few genome-wide studies on heterogeneous cases of multiple nodules for patients with non-small-cell lung cancer (NSCLC). Methods: In this study, we performed genetic profiling using a combination of targeted panel and whole exon genome sequencing (WES) on all lesions of three NSCLC patients with multiple nodules. Results: Driver gene alterations were detected in all lesion samples of the three patients. One patient presented with three nodules, which harbored EGFR L858R, ERBB2 exon 20 insertion and a EML4-ALK fusion. Evolutionary analysis showed strong heterogeneity among the three lesions. The three lesions of patient 2 showed EGFR L858R in two lesions (2A and 2C), and a ERBB2 exon 20 insertions in the other (2B). Mutational signatures and cluster analysis of somatic mutations also showed commonality between sample 2A and 2C, suggesting that they might arise from the same clone. Patient 3 had seven lesions. Analysis of somatic mutations and copy number variations revealed possible route of metastasis. Conclusions: Detailed analysis of genetic mutation characteristics and biological evolution trees showed that there were substantial heterogeneity and distinct evolutionary relationships among the different lesions of the same individual. Consequently, such information could aid in the determination of primary and metastasis of tumor lesions and guide the selection of treatment options.
Bimodal ntrk expression and correlation with activation of PI3K/AKT pathway in lung cancer.
Authors: Ma Wanlong , De Dios Ivan , Antzoulatos Spiraggelos , Estella Jeffrey , Albitar Maher 
Published: May 2020

e21535 Background: N TRK (NTRK1, NTRK2 or NTRK3) fusions are oncogenic drivers of various types of cancer and lead to activation of the PI3K/AKT pathway. Treatment of patients with NTRK fusion using TRK inhibitors, such as larotrectinib or entrectinib, is associated with high response rates ( > 75%). However these fusions are very rare in most common cancers, such as lung and colorectal cancers. We examined the expression levels of NTRK1, NTRK2, and NTRk3 in non-small cell lung cancer using targeted RNA sequencing. We also examined the effects of NTRK overexpression on PI3K/AKT pathway in non-small cell lung cancer. Methods: RNA was extracted from 160 FFPE samples of non-small cell lung cancers and sequenced using targeted next generation sequencing (NGS). The RNA sequencing was based on hybrid capture using a targeted panel of 1408 genes. The number of reads ranged from 5 to 10 million. The RNA levels were measured using Cufflinks as FPKM. Results: NTRK2 fusion was detected in one sample (0.04%). However, overexpression of NTRK1-3 mRNA was more common and showed bimodal expression pattern. Most of the samples (75%) had low levels (median 0.6, 6,79, and 3.17 FPKM for NTR2, NTRK2, and NTRK3, respectively) while the upper 25% of samples had significantly (P < 0.0001) higher levels (Median 2.7, 280, and 17.7 KPFM for NTRK1, NTRK2, and NTRK3, respectively). There was significant difference in expression between the three genes (P < 0.0001). The highest levels were detected in NTRK2 and lowest in NTRK1. In addition, significant variation in alternative splicing was noted in NTRK2. All cases with high expression levels (above the upper quartile) showed significant variation in alternative splicing involving almost all exons. To explore, if high expression correlates with activation of the PI3K/AKT1 pathway, we examined the correlation between high levels (above upper quartile) of NTRK2 with various genes in PI3K/AKT pathway. High levels of NTRK2 mRNA (above the upper quartile) correlated with significantly higher levels of PIK3CA (P < 0.0001) and MDM2 (P = 0.0001). There was no correlation between high expression of NTRK1 or NTRK3 and PIK3CA or MDM2 mRNA. Conclusions: Although fusions involving NTRK1-3 genes in lung cancer are rare, significantly high expression levels can be seen almost 25% of lung cancers. Furthermore, high expression in NTRK2 correlates with activation in the PI3K/AKT pathway. This data suggests that therapy targeting NTRK2 overexpression and/or activation of PI3K/AKT pathway in patients with high NTRK2 mRNA should be explored.
Identification of clinical features to predict the consistency of mutational profiles obtained from plasma and tissue of advanced non-small cell lung cancer (NSCLC) patients.
Authors: Jiao Xiaodong , Qin Bao-Dong , Liu Ke , Wu Ying , Liu Jun , He Xi , Lin Mingqin , Lin Yan , Duan Xiaopeng , Wang Haozhe , Shao Lin , Zheng Jingjing , Zang Yuan-Sheng 
Published: May 2020

e21537 Background: Due to its non-invasiveness and advantage in overcoming tumor heterogeneity, plasma-based genomic profiling is widely used in advanced NSCLC patients for treatment guidance. However, whether the mutational profile derived from ctDNA comprehensively represents that in tumor tissue is the major concern for the application. It has been reported that a variety of factors influence the consistency of mutational profile between plasma and tissue samples. This study explores clinical features which predict the concordance between tissue and plasma samples. Methods: Paired tissue and plasma samples were collected from 79 (stage III and IV) NSCLC patients. Samples were profiled using a 520-cancer-related gene panel. Serum markers such as CEA, CA199, SCC and NSE were collected. Results: All tissue samples except for 1 (98.7%) had mutations detected from this panel. 68 plasma samples (86%) had mutations detected from this panel. The overall concordance of mutation between plasma and tissue samples was 43%; and the concordances for point mutation and copy number variations were 60.2% and 15%, respectively. The concordance for 8 classic lung cancer driver genes and druggable mutations were 77.2% and 34.2%, respectively. Next, we explore the correlation of serum biomarkers and the concordance rate. Univariate analyses revealed that CA19-9 (P < 0.001) and CEA (P = 0.01) were significantly associated with the concordance rate of actionable mutations. Using CEA > 5ng/ml as a cutoff, 43.1% patients having higher CEA level harbored an identical mutation profile between plasma and tissue vs only 20.8% patients with lower CEA level had an identical mutation profile (p = 0.01). Furthermore, 75% patients with CA 19-9 > 39U/ml harbored an identical mutation profile between plasma and tissue vs 22.8% patients with CA19-9 £ 39U/ml (P < 0.001). Combining both CEA and CA19-9 can effectively predict the concordance (p < 0.001); 85.7% of patients with CEA and CA19-9 levels above the cutoff have identical mutation profile and only 34.2% patients with either one or both below the cutoff have identical mutation profile (p < 0.001). Conclusions: We identified the clinical and molecular factors which showed promising value in predicting the consistency of mutational profile between plasma and tissue in NSCLC patients. Plasma samples of patients with high CEA ( > 5ng/ml) and CA19-91 ( > 39U/ml) can comprehensively reflect the mutation profile of tumor samples. Tissue biopsy is not necessary for such patients.
Comprehensive genomic profile by Foundation Medicine test in guiding routine decisions for second-line treatment in advanced non-small cell breast cancer (NSCLC): Preliminary results of lung-ONE study.
Authors: Rojo Federico , Felip Enriqueta , Juan-Vidal Oscar , Campelo Rosario Garcia , Aguiar Bujanda David , Terrasa Josefa , Lopez Castro Rafael , Calles Antonio , Paredes Alfredo , Bernabe Caro Reyes , Barneto - Aranda Isidoro C. , Campillo Juana , Garcia Palacios Luis , De Castro Javier 
Published: May 2020

e21555 Background: Lung-ONE study aims to determine the clinical utility in making decisions on planned 2nd line therapy in advanced NSCLC based on a comprehensive genomic profile (CGP) test as FoundationOne CDx or FoundationOne Liquid and describe alterations found on these patients. Methods: Lung-ONE included advanced/metastatic NSCLC patients being treated on first-line, with molecular diagnostic wild-type (or unknown) for at least ALK, EGFR, and ROS-1 genes. Patients treated with targeted therapies or immunotherapy were excluded. This interim analysis describes the findings of CGP from patients of Lung-ONE with driver genomic alterations (GAs) and the investigators decision to change the planned second line treatment or not. Patients continue being followed-up for up to 2 years. Results: As of November 15 2019, 152 patients were included. At the time of sampling, 90.7% had received ≥2 different chemotherapy regimens and other therapies. Main testing for ALK and ROS-1 was IHC in 91.4% and 73.8%, respectively; and for EGFR, it was qPCR in 99.3%. Planned 2nd-line based on routine molecular profile was chemotherapy and, mainly checkpoint inhibitors (61.7%). CGP was assayed on 102 (67.1%) tissue specimens and 50 (32.9%) blood samples. Of the 1,581 GAs identified in 141 patients, 541(34.2%) were potential drivers in 131. The most frequently mutated genes were TP53 in 72(55%) patients and KRAS in 52(40%). TMB and MSI signatures were calculated on 82 patients. 21% had < = 16 mut/Mb. Other GAs of interest are presented in table. Therapeutic orientations were recommended for 116/152(76.8%) patients. In 39/151(25.8%) patients the GAs had approved drugs in NSCLC or other tumor types. CGP outcomes, would be used by 27% of oncologists to guide targeted 2nd-line. Conclusions: CGP detected mutations that are informative for choosing personalized treatment in 25%. CGP demonstrates the ability of detect druggable genomic alterations missed at diagnosis opening new treatment options. [Table: see text]
Next-generation sequencing of tissue and liquid rebiopsy favors post-progression outcomes of EGFR T790M-positive NSCLC patients treated with osimertinib.
Authors: Cheng Jiangtao , Yao YiHui , Gao Yu-Er , Zhang Shi-Ling , Chen Hua-Jun , Wang Zhen , Yan Hong-Hong , Zhou Qing , Tu Hai-Yan , Zhang Xu-Chao , Su Jian , Xie Zhi , Wu Yi-Long , Yang Jin-Ji 
Published: May 2020

e21563 Background: Osimertinib is standard of care for patients with advanced non–small-cell lung cancer (NSCLC) carrying acquired epidermal growth factor receptor ( EGFR) T790M mutation. However, few studies have been conducted to investigate the impact of rebiopsy on clinical outcomes after resistance to osimertinib. We evaluated whether next-generation sequencing (NGS) of tissue and liquid rebiopsy could favor post-progression outcomes of T790M-positive advanced NSCLC patients treated with osimertinib. Methods: Immediately just after resistance to second- or further-line osimertinib, advanced NSCLC patients with acquired EGFR T790M mutation were retrospectively divided into the NGS and non-NGS groups according to whether they underwent NGS of tissue or liquid rebiopsy. The co-primary endpoints were post-progression survival (PPS) defined as the time from osimertinib resistance to subsequent-line treatment resistance, and post-progression overall survival (pOS) defined as from osimertinib resistance to death or end of the last follow-up. Multivariable analyses were done using Cox proportional hazards regression model and log-rank test. Results: Between January 2017 and July 2019, 89 patients (62 vs. 27 for the NGS and non-NGS groups respectively) were eligible for final analyses. In the NGS group, 3.2% (2/62) underwent tissue rebiopsy only, 29.0% (18/62)only had liquid rebiopsy, and 66.8% (42/62)with both tissue and liquid rebiopsy.The NGS group received more targeted or combined therapy after resistance to osimertinib (62.9% vs. 40.8%, P= 0.053). The NGS group was significantly superior to the non-NGS group in the co-primary endpoints. The median PPS was 6.1 vs. 2.7 months (hazard ratio [HR], 0.49; 95%CI, 0.30 to 0.80; 2-sided log-rank P= 0.004). Meanwhile, the median pOS was 11.7 vs. 6.8 months (HR, 0.50; 95%CI, 0.29 to 0.85, 2-sided log-rank P= 0.009). Conclusions: Providing more opportunities for individualized treatment, NGS of tissue and liquid rebiopsy favors post-progression outcomes of EGFR T790M-positive advanced NSCLC patients treated with osimertinib.
EGFR tyrosine kinase inhibitor therapy continuation with high-dose hypofractionated radiotherapy in EGFR-mutated non-small cell lung cancer (NSCLC) patients with oligoprogressive disease.
Authors: Santarpia Mariacarmela , Valerio Maria Rosaria , Borsellino Nicolò , Girlando Andrea , Mancuso Gianfranco , Altavilla Giuseppe , Gebbia Vittorio 
Published: May 2020

e21580 Background: EGFR tyrosine kinase inhibitors (TKIs) represent the standard first-line therapy for advanced non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. However, despite initial marked responses, tumors invariably develop acquired resistance to TKIs. Oligoprogression is commonly observed during treatment with oncogene-directed therapies, including EGFR TKIs, and refers to patients who experience disease progression only in limited sites as a result of heterogeneous mechanisms of resistance. The use of local ablative treatments for these resistant lesions may extend the duration of TKI therapy and potentially improve long-term disease control and survival. We e retrospectively analyzed the efficacy of EGFR TKI therapy continuation with high-dose hypofractionated radiation therapy (RT), in EGFR-mutant NSCLC patients with oligoprogressive disease. Methods: Patients with metastatic EGFR mutant NSCLC who developed oligoprogression during first-line treatment with gefitinib were included in this analysis. We evaluated progression-free survival 1 (PFS 1), defined as the time from initiation of TKI therapy until development of oligoprogression or death, and PFS 2, defined as time of focal progression until further progression of disease or death. Overall survival and safety were also assessed. Results: Thirty-six patients were included in the study. The median PFS 1 was 12.5 (4.0-23.2) months. High-dose hypofractionated RT consisted of intensity-modulated RT in 23 patients (64%) and stereotactic radiotherapy in 13 cases (36%). The median PFS 2 was 6.3 (2-12.5) months. Overall survival was 38.7 months (9.0-46.3). The treatment was well-tolerated and no patient had to discontinue TKI therapy because of adverse events during radiotherapy. Conclusions: Our therapeutic strategy, including high-dose hypofractionated RT in addition to TKI therapy, was feasible in the clinical setting and was associated with significant prolongation of disease control and improvement of survival outcomes, while being associated with manageable side effects. Our study further support the use of definitive therapeutic approaches in oligoprogressive disease, especially in oncogene-driven tumors. Molecular profiling of metastatic sites remains crucial to identify novel biomarkers, involved in the development of acquired resistance and oligoprogression, that may be useful to select patients for local treatments.
Real-world testing compliance to NCCN guideline and factors of underutilization in U.S. community clinics.
Authors: Bernicker Eric , Xiao Yan , Abraham Anup , Redpath Stella , Engstrom-Melnyk Julia , Croix Denise , Yang Baiyu , Shah Roma , Madala Jaya , Allen Timothy 
Published: May 2020

e21592 Background: Over the last 10 years, guideline recommendations for testing advanced non-small cell lung carcinomas (aNSCLC) have rapidly evolved with the identification of driver mutations and associated therapies. A retrospective study of the testing rates for ALK was initiated to understand real world adherence to guidelines. Methods: A retrospective study of the testing rates (negative category = not tested/unknown testing status) for ALK utilizing the nationwide Flatiron Health electronic record-derived de-identified database was initiated. Patients diagnosed with NSCLC (Stage IIIB-IV) were initially included (41,728 patients from Jan 2012 to May 2019) to describe the trend of ALK testing in community setting. An increase in ALK testing was seen from 59.5% to 84.1% of NCCN guideline eligible patients from 2012-2019. There was also an increase in the number of ineligible patients (smokers with squamous histology) tested (15.6% in 2012 to 50.8% in 2019). This 2012-2019 patient population was then limited to diagnosis from Jan 2015 to May 2019 to assess factors related to test utilization. In 26,617 aNSCLC patients, 75% were ALK testing eligible (by NCCN guidelines) with one quarter ineligible. Multivariable logistic regression analysis was used to assess clinical and demographic factors for impact on testing rates. Results: Both histology type and smoking status played an important role impacting ALK testing rate. Compared to non-squamous non-smokers (9.3% ALK-positive, 87.9% testing rate), non-smokers with squamous cell histology had a relatively high rate of ALK mutation (3.3%) but a low testing rate (55.03%) (Odds ratio (OR) 7.6, 95% CI 5.6-10.4). Other histology type and smoking status also had lower testing rate, including non-smoker with NSCLC non-specific type (OR 1.8, 95% CI 1.1-3.2), and smoker with non-squamous type (OR 1.5, 95% CI 1.3-1.7). Additional factors related to underutilization were patients with poorer ECOG scores and earlier stage at diagnosis. Demographic characteristics that also played a role in underutilization were older age ( > 50 yrs), non-commercial insurance, male, and patients diagnosed before 2017. Conclusions: This analysis of real world data shows that test utilization has increased but there remains room for improvement. While testing ineligible patients is an inefficient use of resources (smokers with squamous histology), smokers with a small biopsy should be tested as they might be harboring an actionable driver mutation. Eligible patients still remain untested and potentially missing therapeutic options.
Final analysis of a phase II, open label, randomized study of osimertinib versus osimertinib plus carboplatin/pemetrexed for patients with locally advanced or metastatic non-small cell lung cancer whose disease has progressed with previous EGFR-TKI and whose tumours harbour a T790M mutation (LOGIK1604/NEJ032A).
Authors: Tanaka Kentaro , Asahina Hajime , Okada Morihito , Uchida Takahiro , Watanabe Kana , Hamai Kosuke , Harada Taishi , Tsubata Yukari , Sugawara Shunichi , Kobayashi Kunihiko , Sugio Kenji , Oizumi Satoshi , Okamoto Isamu 
Published: May 2020

e21594 Background: Osimertinib is now available not only as a second line treatment for the patients with EGFR and T790M-mutation positive non-small cell lung cancer (NSCLC) after initial tyrosine kinase inhibitors (TKIs) but as a first line treantment for those who are TKI-naive. The efficacy and the safety of osimertinib plus palatinum-based chemotherapy has not yet been evaluated. Methods: This phase 2, open-label, randomized study enrolled adult patients (pts) with clinical stage IIIB or IV, or postoperative recurrent NSCLC harbouring susceptible EGFR and T790M mutations after preceded EGFR-TKI failure. Pts were randomly assigned to receive either an osimertinib [80 mg/day 1-21; q3w] or a combination of osimertinib [80 mg/day 1-21] with carboplatin/pemetrexed (hereafter combination) [area under the curve (AUC) = 5 and 500 mg/m2 day 1; q3w]. The primary endpoint was progression-free survival (PFS). Secondary endpoints included incidence of adverse events, response rate and overall survival. As indiction of osimertinib was expanded to a first line, we amended the protocol to discontinue the enrollment and perform final analyses. Results: From October 2016 to January 2019, 62 pts were enrolled [31 pts osimertinib; 31 pts combination] (median age 68 (37-80); 53.2% male; 83.3% stage IV; 100% adenocarcinoma; 59.7% exon 19 deletion and 40.3% L858R; 45.2% never smoker). The rate of grade (G) ≥ 3 treatment-related adverse events was 32.2% in the osimertinib group and 83.9% in the combination group. Neutropenia, anemia and thrombocytopenia were more common in the combination group and the rates of G ≥ 3 were 0%, 0% and 6.4% in the osimertinib group and 38.7%, 25.8% and 29.1% in the combination group, respectively. Three episodes (9.7%) of G ≥ 3 infection and one episode (3.2%) of G ≥ 3 febrile neutropenia were uniquely observed in the combination group, however, these were well managed. Two episodes (6.5%) of G ≥ 3 pneumonitis was observed only in the osimertinib group. Exaggeration of adverse events specific for osimertinib or any unknown adverse event was not observed in the combination group. Final PFS analysis is to be demonstrated in the presentation. Conclusions: Combination of osimertinib with carboplatin and pemetrexed demonstrated safety in patients with EGFR and T790M mutation-positive NSCLC and the efficacy should be validated in the future phase 3 study. Clinical trial information: 000024438.