bluuebunny/crossref_metadata_2025 huggingface dataset:
Intratumoral heterogeneity and tumor evolution of small cell lung cancer through multi-regional sequencing.
Authors: Zhang Yaxiong , Zhou Ningning , Zhou Huaqiang , Song Mengmeng , Li Pansong , Guan Yan-Fang , Xia Xuefeng
Published: May 2020

e21103

Background: Small cell lung cancer (SCLC) is a type of aggressive malignancy with poor prognosis, accounting for 15% of lung cancers. Intratumoral heterogeneity (ITH) has been investigated in lung adenocarcinoma or squamous cell carcinoma, but its role in SCLC still remains unclear. Exploring ITH and tumor evolution of SCLC is essential for its treatment and prognosis. Methods: 102 multi-regional tumor tissues were collected from 34 operative SCLC patients (pts) before systemic therapy during Sep. 2009 to Sep.2018 from Sun Yat-sen University Cancer Center. All of the enrolled cases were confirmed as SCLC by immunohistochemistry. We performed whole-exome sequencing (WES) of all the tumor tissues and assessed the ITH using clonal and subclonal somatic mutations or copy number variants. ITH was defined as the proportion of subclonal genetic alterations of all. The relationship between ITH and overall survival (OS) was also explored. Results: Among the enrolled 34 SCLC pts, the median age was 64 year. 28 pts had the smoking history. 23 pts received adjuvant therapy after surgery. Stage I-II and III-IV pts accounted for 50% respectively. The most frequent mutated genes were TP53 (88%), RB1 (70%), TTN (68%), TCEB3CL (65%), MUC16 (56%), and all of them were clonal. The median overall ITH was 0.36 (ranging from 0 to 1), while the mutational ITH and the CNV ITH were 0.50 (0.22 to 1) and 0.49 (0.22 to 1). Univariate analysis revealed that postoperative treatment (HR = 0.27, 0.07-0.97, p= 0.006) and higher CNV ITH (HR = 0.28, 0.08-0.99, p= 0.009) were significant positive predictors of OS, while higher mutational heterogeneity was not associated with OS (HR = 3.34, 0.91-12.25, p= 0.21) significantly. Conclusions: TP53, RB1, TTN, TCEB3CL and MUC16 were probably clonal mutations as early events in SCLC evolution. CNV ITH might be a prognostic predictor in SCLC, which should be verified in a large-sample cohort.
Is there a role for hypofractionated thoracic radiotherapy in limited-stage small cell lung cancer? a propensity score matched analysis.
Authors: Zayed Sondos , Chen Hanbo , Ali Emma M , Rodrigues George , Warner Andrew , Palma David A. , Louie Alexander V
Published: May 2020

e21107

Background: Concurrent chemoradiotherapy is the standard of care for limited-stage small cell lung cancer (LS-SCLC). While conventional fractionation (CF) and hyperfractionation are the most commonly used radiotherapy schedules worldwide, hypofractionation (HF) continues to be a standard radiation regimen used in several countries. In the absence of randomized evidence comparing CF and HF, the aim of this study was to compare overall survival (OS), progression-free survival (PFS), and toxicity outcomes for CF and HF in LS-SCLC. Methods: In this single institution retrospective review, consecutive LS-SCLC patients treated between 2000-2013 with HF (40Gy/15, 45Gy/15, 45Gy/20 fractions) or CF (60Gy/30 or 66Gy/33 fractions) were included. Propensity scores were generated using a multivariable logistic regression model. Patients were matched on a 1:1 ratio with a caliper distance of 0.20. OS and PFS were estimated using the Kaplan-Meier method with differences evaluated using log-rank tests. As a sensitivity analysis, univariable and multivariable Cox regression was performed in all unmatched patients. Logistic regression was performed to identify predictors of all pulmonary and esophageal adverse events. Results: In the 117 patients, there were significant baseline differences between the CF and HF cohorts. Patients who received CF were older, smoked more often concurrently with treatment, had higher ECOG performance status, different T and N stage patterns, and more commonly received concurrent chemoradiotherapy and prophylactic cranial irradiation. After propensity score matching, 72 patients were included, 36 in the HF and CF cohorts respectively. No statistically significant difference was noted between matched HF and CF cohorts for OS (P = 0.724) or PFS (P = 0.862). Similarly, multivariable Cox regression revealed no differences in OS (P = 0.886) or PFS (P = 0.717) between HF and CF in all unmatched patients. There was no difference in any pulmonary (P = 0.350) or esophageal (P = 0.097) adverse events between matched HF and CF cohorts. Skin adverse events were significantly higher for CF (41.7%) compared with HF (16.7%, P = 0.020) in matched patients. No grade 5 adverse events were observed. Conclusions: In this propensity score matched comparison of HF and CF in LS-SCLC patients who underwent curative-intent radiation treatment, HF and CF were associated with comparable OS, PFS, and toxicity outcomes. HF may therefore be a reasonable alternative to CF, should its efficacy be confirmed in prospective studies.
Real-world data on liquid biopsies utilization in lung cancer patients in the community setting: The Mount Sinai experience.
Authors: Dvir Kathrin , Galarza Fortuna Gliceida , Haines Joel M. , Drusbosky Leylah , Febres-Aldana Christopher , Gines Paulina , Rodriguez Estelamari
Published: May 2020

e21502

Background: Liquid biopsy describes the extraction of circulating tumor DNA (ctDNA) from peripheral blood via next-generation-sequencing (NGS). The yield of adding plasma-based NGS to tissue NGS for the detection of Actionable Mutations (AM) have been reported scarcely and additional “real world” data is needed. Methods: In this retrospective data review, we included patients with non-small cell lung cancer (NSCLC) who had plasma NGS genomic testing ordered between Nov 2014 and July 2019, as part of routine management. Plasma testing was performed using Guardant360 commercial platform and was analyzed for therapeutically AM in: EGFR, ALK, MET, BRCA1, BRCA2, KRAS, ROS1, RET, ERBB2, BRAF, and NTRK2. Results: Over a period of 5 years, 337 samples taken from 279 patients were sent for ctDNA NGS testing. The median age at diagnosis was 73 years [range 36-93, SD:10.4], 51% (N=141) were males and 49% (N=138) were females. Excluding synonymous mutations and variants of unknown significance, 239 samples (71%) and 201 patients (72%) had 705 somatic mutations. Of them, 36% (N=254) were therapeutically actionable and were detected in 139 samples (58%), taken from 106 patients (53%). Commonly detected AM were EGFR (N=127; 50%), KRAS (N=61; 24%), BRAF (N=24; 9.5%), MET (N=23; 9%), RET (N=5; 1.9%), BRCA1 (N=5; 1.9%), BRCA2 (N=4; 1.6%), ERBB2 (N=4; 1.6%) and ALK (N=1, 0.4%). None of the samples had mutations in ROS1, NTRK2. One patient had Microsatellite instability (MSI). Common co-occurring mutations were EGFR and BRAF (N=14), EGFR and MET (N=13) and MET and BRAF (N=10) (p<0.001). Common mutually exclusive mutations were KRAS and EGFR (p<0.001). Tissue NGS analysis was performed in 62/106 patients (58%), with AM found in 45 patients (72%). Concordance agreement in AM between plasma and tissue NGS modalities was detected in 39/45 patients (87%) and was demonstrated in EGFR (N=25), KRAS (N=11), BRAF (N=2) and MET (N=1). In the reminder 6 patients (13%), tissue NGS was discordant from their plasma NGS results. In 44/106 patients, for whom tissue sampling was not performed, utilizing plasma NGS increased AM detection yield by 41%. Conclusions: Integration of plasma NGS testing into the routine management of NSCLC patients demonstrated substantial yield of therapeutically targetable mutations detection rate, when tissue NGS was not available.
Neoantigen screening identifies EGFR L858R mutation immunogenicity in 1862 Chinese NSCLC patients.
Authors: Lin Jin , Chen Yu , Chen Gang , Jun Liu , Hao Shiguang , Xiong Jia-ni , Lan Bin , Xu Yaping , Guan Yan-Fang , Guo Zengqing , Chen Lin , Chen Li-zhu , Xia Xuefeng
Published: May 2020

e21512

Background: Therapeutic vaccines targeting mutation-derived neoantigens prime T-cell responses and deliver long-term clinical benefit to patients. Last year we reported EGFR L858R mutation could be a possible target for individual-independent vaccine in 799 Chinese patients with non-small cell lung cancer (NSCLC). Here we verified the findings and explored possible immunological mechanisms in a larger sample size of 1862 Chinese NSCLC. Peripheral blood or normal tissue was used as control. Methods: DNA sequencing data was acquired using our targeted 1021-gene panel and HLA-I genotyping was determined based on DNA sequencing by OptiType v1.0. The peptide-HLA binding affinity was predicted with netMHCpan v4.0. Neoantigen was identified if the IC50 MT < 500 nM and IC50 WT > 500 nM, furthermore, IC50 MT < 50 nM was considered as strong-binders. Results: EGFR (50.05%) was the most prevalent mutated gene, with 22.61% and 13.16% harboring L858R mutations and E746_A750del respectively. HLA typing showed HLA-A*11:01(42.59%) was the top one allele and HLA-A*33:03(12.94%) ranked 12th. The combination of EGFR L858R and HLA-A*33:03 had both relatively strongest binding affinity (IC50 MT = 22.9 nM and IC50 WT = 12734.0 nM, 2.93%) and highest shared frequency (2.93%). In terms of mechanism, we examined 7 of 1862 (0.37%) B2M gene mutation and 1092 of 1731 (63.1%) HLA-I LOH (loss of heterozygosity) in our population, but didn’t see any statistical difference between L858R subtype and other position mutations in EGFR. We also calculated 26 immune cell types’ signature scores from Chinese CHOICE study and found L858R subtype was associated with elevated level of pDC (KW-test p = 0.02) and lower level of neutrophils signature(KW-test p = 0.07) compared with exon 19 deletion and other uncommon mutations of EGFR. Conclusions: (1) Targeting EGFR L858R mutation in patients with HLA-A*33:03 allele appeared to be valuable for the neoantigen-based vaccine designed for Chinese NSCLC patients. (2) The specific immunogenicity of L858R seemed to be little influenced by B2M mutation and HLA-I LOH which were important factors for neoantigen presentation. (3) High pDC and low neutrophils infiltration might contribute to the inhibitive microenvironment associated with L858R mutation.
Using real-world data to investigate time-dependent blood count response to PD-1 and PD-L1 inhibitors and its impact on survival in advanced non-small cell lung cancers.
Authors: Ayers Kristin , Liu Zongzhi , Ma Meng , Lee Kyeryoung , Newman Scott , Li Li , Zhou Xiang , Mullaney Tommy , Redfern Arielle , Jappe Whitney , Zimmerman Michelle , Prentice Tony , Oh William , Schadt Eric , Li Dan , Chen Rong
Published: May 2020

e21514

Background: Although some advanced non-small cell lung cancer (aNSCLC) patients respond favorably to immune checkpoint inhibitors, a larger portion either do not respond or experience negative side effects. At present, there is no consensus on how to best predict response to immunotherapy (IO) agents. Complete blood count (CBC) data have shown correlation with both progression and survival for patients treated with IO. However, previous studies have been relatively small, or did not focus on aNSCLC. Given CBCs are measured routinely for every patient throughout their course of therapy, we used real-world data (RWD) to assess the biomarker potential of CBCs in predicting response at the start and through the course of therapy. Methods: We performed a retrospective cohort study of 11,138 lung cancer patients treated at hospitals in the Mount Sinai Health System of whom 249 aNSCLC and were treated with anti-PD1/PD-L1 therapy. We extracted and harmonized medical record data using an automated abstraction engine and evaluated the impact of changes in CBCs, including eosinophils, lymphocytes, monocytes, neutrophils, red blood cells and platelets after treatment initiation. Time to treatment discontinuation (TTD) and overall survival (OS) were our clinical endpoints. Results: Abnormal baseline levels of monocytes, neutrophils, and red bloods cells were associated with OS; counts taken between 2-8 weeks were modestly to significantly associated with poorer OS, with hazard ratios ranging from 1.7-4.7. Most strikingly, neutrophil levels above 7 (HR = 4.3, p = 3.2*10−10, 95% CI = 2.7-6.7) and a neutrophil-to-lymphocyte ratio > 5 (HR = 3.4, p = 8.0*10−8, 95% CI = 2.2-5.4) were associated with poorer OS. For those with normal neutrophil levels at baseline, progressing to high levels at 2-8 weeks resulted in a hazard for OS of 5.0 (p = 4.4*10−8, 95% CI = 2.8-9.0). Those with progression are more likely to have high neutrophil levels at baseline, or an increase in neutrophil levels from normal to high levels between baseline and 2-8 weeks or 8-14 weeks. Our results remained consistent even after controlling for factors that may affect neutrophil levels including concurrent chemotherapy, administration of neutropenia medications, or concurrent infections. Repeating the analysis with TTD as the primary endpoint showed similar but less significant trends. Conclusions: RWD showed changes in blood cell counts after anti-PD1/PD-L1 therapy were associated with OS in aNSCLC and show promise as a predictive biomarker.
Clinical and molecular characteristics of the patients in the liquid biopsy study in mEGFR-NSCLC in a Spanish population (OPH-1).
Authors: Franco Fernando , Serna Roberto , Sanchez Alfredo , García Girón Carlos , Domine Manuel , Camps Carlos , Sanchez Torres Jose Miguel , Oramas Rodriguez Juana Maria , Chara Velarde Luis Enrique , Ortega Ana Laura , Sala Maria Angeles , Hernandez Berta , Sereno Maria , Bosch-Barrera Joaquim , Padilla Airam , Balsalobre Yago Jose , Blanco Remei , Mielgo Xabier , Romero Atocha , Provencio-Pulla Mariano
Published: May 2020

e21515

Background: The liquid biopsy (LB) is an important tool in the diagnostic and follow up of the patients with non-small cell lung cancer (NSCLC) and can provide big information about the mutational variability of the disease during of the treatment. Methods: We conducted a multicenter study with 200 patients with EGFR-mutated NSCLC, treated with first-line TKI therapy. We analyse the ctDNA by dPCR pre-treatment, at 8 weeks, at 7 months and at the progression of the disease (PD). Results: A total of 200 patients (60% women / 40% men) were included. The median of age was 68-year. The never smokers were 56% and 34% ex-smokers. 92% of the cases were adenocarcinomas. According to the stage of the disease, 52% were stage IVB, 38.5% stage IVA and 9.5% unknown. The first-line treatment was afatinib in 47.5%, erlotinib in 21.5% and gefitinib in 31%. According to the type of sensitivity mutation, 61.5% corresponded to Del19, 32% to L858R, 2.5% to G719X and 2.5% to L861Q. At the time of diagnosis, 63% had pulmonary metastatic involvement and 42.5% liver metastasis. At the time of data analysis, 66% of the patients had some progression of the disease (PD) and 37% died. 68% of the patients with Del19 received afatinib, while 20% of the patients with L858R received afatinib, 54.5% erlotinib and 32% gefitinib (p = 0.02). With a median follow-up of 20 months, progression-free survival was 11.8 months, without any differences according to the treatment (p = 0.93). The groups with worse PFS included: the squamous histology (HR 5.7; 95%CI 2.04-15.91, p = 0.001), the G719X mutation (HR 3.36; 95%CI 1.21-9.25, p = 0.019) and the liver metastasis (HR 1.65; 95%CI 1.01-2.68, p = 0.042). The sensitizing mutation was detected in the 80.8% of the patients in the LB by dPCR and the T790M in 2%. However, in the first control only was detectable in 18.5%. At the time of PD, the percentage of detection of T790M raised to 52.3%, and the sensitizing mutation 79.44%. At that moment, patients who developed T790M were mostly never smokers (66%, p = 0.006) and had Del19 (66%). Patients with bone progression developed T790M in 60.4% (p = 0.014) and hepatic 27% (p = 0.012). Conclusions: We concluded that the clinical characteristics of the patients of the OPH study are consistent with the previous reported in the Caucasian population and the subgroups with the worst prognosis include the squamous histology, the G719X mutation and the liver metastasis.
Association of HLA class 1 homozygosity with unfavorable clinical outcomes in patients with non-small cell lung cancer (NSCLC) treated with PD-1 inhibitor as first-line therapy.
Authors: Chae Young Kwang , Lee Dongyup , Park Jonghanne , Choi Horyun , Gim Gahyun , Cho Sukjoo , Kim Leeseul , Oh Youjin , Kang Cyra Y , Viveiros Pedro Antonio Hermida de
Published: May 2020

e21519

Background: Homozygosity at human leukocyte antigen class I (HLA-I) locus has been reported to be an unfavorable predictive biomarker of second line or beyond immunotherapy in patients with different types of cancer including melanoma and NSCLC. The linkage between HLA-I homozygosity and survival outcomes in NSCLC patients treated with first-line immunotherapy has not been reported. Methods: Next generation sequencing with HLA genotyping was performed for patients with unresectable stage III or IV NSCLC treated with pembrolizumab plus chemotherapy as first line (N = 25). Progression free survival (PFS) was compared between HLA-I homozygous (defined as homozygosity in at least one locus A, B, or C) and heterozygous patients. Kaplan-Meier curves were built and Log-rank test was used to compare unadjusted survival statistics between the groups. Cox Proportional Hazards were then used to adjust for potential confounders; age, sex, and tumor mutation burden status (TMB, above vs. below median). Results: The median follow up time was 259 days [interquartile range,163 to 350]. Among 25 enrollees, 21 patients (84%) were HLA-I heterozygous and 4 patients (16%) were HLA-I homozygous. Treatment response was not available in 6 patients with HLA-I homozygosity. Among 15 patients with HLA-I homozygosity, 4 patients (26.7%) had partial response (PR), 7 patients (46.7%) had stable disease(SD), and 4 patients (26.7%) had progressive disease (PD). Among 4 patients with HLA-I heterozygosity, 1 patient (25%) had PR, 1 patient (25%) had SD, and 2 patients (50%) had PD. The disease control rates (PR and SD) were 73.4% in heterozygous group and 50% in homozygous group. The heterozygous group showed longer median PFS than the homozygous group (19 vs. 9.4 months, Log-rank p = 0.14). Patients with HLA-I homozygosity demonstrated shorter PFS (HR = 2.35, 95% CI = 0.56-9.9, p = 0.25). Adjusted HRs controlled for age, sex, and TMB were 3.6[0.65-20], 2.3[0.55-9.9] and 1.7[0.34-8.6] respectively. Conclusions: We observed a trend toward an inverse association between HLA-I homozygosity and survival outcomes in patients with NSCLC treated with first-line immunotherapy. Further perspective studies to validate such relationship are warranted.
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.
Association of PD-L1 expression with hotspot mutations in non-small cell lung cancer (NSCLC).
Authors: Wan Renping , Zhang Xiaoni , Qu Hongyue , Li Hui , Li Yingmei , Xu Mingyan , Xiao Yun
Published: May 2020

e21604

Background: PD-L1 is of great interest in many clinical trials on immunotherapy as a promising biomarker, however, its role in targeted therapy and correlation with hotspot mutations remains unclear. Methods: From May 6th 2019 to Jan 27th 2020, 609 NSCLC patients were prospectively enrolled. Targeted deep sequencing (~3000X) with a 605-gene panel was performed on tumor and blood sample from each patient. The expression of PD-L1 was tested by immunohistochemistry. PD-L1 expression level was defined as negative ( < 1%), low (1%~50%), and high (≥50%). Results: In the total 609 patients, the expression of PD-L1 was negative in 36.9% (n = 256), low in 51.7% (n = 315) and high in 11.3% (n = 69) of them. In 440 patients harboring hotspot mutations, 35.0% (n = 154) of them were identified as PD-L1 negative, 52.3% (n = 230) as PD-L1 low and 12.7% (56/440) as PD-L1 high. In 169 patients without hotspot mutations, there were 42.0% (71/169) of patients with negative PD-L1 expression, 50.3% (85/169) with low PD-L1 expression and 7.7% (13/169) with high PD-L1 expression. Mutation frequencies of several hotspot mutations were summarized in Table. Conclusions: This study showed that PD-L1 expression was associated with some hotspot mutations, such as BRAF_p.V600E, KRAS_p.G12/G13/Q61 and amplification of MET. Although the biological mechanism of this association is yet to be investigated, combination of hotspot mutations and PD-L1 expression could be a future direction in biomarker studies. [Table: see text]
Intergration of common clinical and laboratory parameters for predictive modeling of outcome with immune checkpoint inhibitors (ICIs) in patients (pts) with Nnon-small cell lung cancer (NSCLC).
Authors: Rounis Konstantinos , Makrakis Dimitrios , Papadaki Chara , Monastirioti Alexia A , Vamvakas Lampros , Kalbakis Kostas , Gourlia Krystallia , Xanthopoulos Iordanis , Mavroudis Dimitrios , Agelaki Sofia
Published: May 2020

e21609

Background: We prospectively recorded common clinical and laboratory parameters of pts with metastatic NSCLC treated with 2nd line ICIs to evaluate their potential value in a clinical outcome prediction model. Methods: Data on patient (age, PS, BMI) and disease characteristics (histology, sites/number of metastases), smoking status, use/duration of co-medications [proton pump inhibitors (PPIs) inhalational/p.os steroids, antibiotics (ATB)], laboratory values [neutrophil/lymphocyte ratio (NLR), LDH] and response to previous therapy were prospectively collected. Pts were categorized as having steroids if they had received steroids > 10mg for ≥10d (starting from 15d before or within the first 3 months of treatment). Prolonged ATB administration was defined as ATBs ≥14d (30d before or within the first 3 months). JAD Bio (www.jadbio.com), an Automated Machine Learning service that analyzes biological data with emphasis on feature selection was used to create predictive models. Results: 66 pts were evaluated; median follow up time was 6.37 months. 15.2% of patients had PR, 34.8% SD and 50% PD. Median PFS and OS were 3.5 and 6.77 months, respectively. Steroids had negative impact on disease stabilization (PR+SD) rates (p = 0.042) and PFS (p = 0.013) but not OS (p = 0.051). ATBs negatively affected RR (p = 0.046) only, whereas, prolonged ATB exposure was associated with lower RR (p = 0.007), PFS (p = 0.0001) and OS (p = 0.001). In multivariate analysis, steroids [HR = 2.54 (CI:1.23-5.29, p = 0.012)], prolonged ATBs [HR = 3.46 (CI:1.72-6.95, p = 0.0001)], liver HR = 2.92 (CI:1.45-5.78, p = 0.003) and bone HR = 2.06 (CI:1.041-4.10, p = 0.038) metastases independently predicted for shorter PFS. Only prolonged ATBs [HR = 2.52 (CI: 1.39-4.54, p = 0.002)] and bone metastases [HR = 2.26 (CI: 1.23-4.17, p = 0.009)] independently predicted for shorter OS. Analysis of the investigated parameters by JAD Bio predicted disease stabilization with an accuracy of 71%. Importantly, PDL-1 status was not included due to high rates of missing data. Conclusions: Our results corroborate previous evidence on the detrimental role of prolonged ATB administration on ICIs efficacy, possibly related to perturbation of the gut microbiota. Modeling, including other significant parameters from larger patient cohorts, could result in a robust estimation of outcome.