bluuebunny/crossref_metadata_2025 huggingface dataset:
MCM4 as a prognostic biomarker of early-stage lung cancer.
Authors: Sriuranpong Virote , Luangdilok Sutima , Chantranuwatana Poonchavist , Leeladejkul Nussara , Pornpatanarak Nopporn , Benjacholamas Vichai , Sitthideatphaiboon Piyada , Vinayanuwattikun Chanida - , Pisitkun Trairak
Published: May 2020

e21033

Background: Prognostic biomarker in early-stage lung cancer is less well defined. Despite early detection, one-third of patients with completely resected early-stage lung cancer without lymph node involvement have a recurrence. Our main objective is to investigate potential biomarkers useful in classification and predicting prognosis of this early-stage lung cancer, particularly in lymph node-negative subgroup. Methods: In discovery phase, we performed proteomic profiling on 60 lung cancer tissues to distinguish solid versus non-solid adenocarcinoma. Relative protein quantification was analyzed using Tandem Mass Tag mass spectrometry. In validation phase, tumor tissues from an additional cohort were analyzed by immunohistochemistry in conjunction with quantitative image analysis to confirm the differential expression of significantly altered proteins, including MCM2, MCM4, MCM6, SCAMP3, DPP4 and MYH11. Prognostic potentials of each biomarker were analyzed with univariate and multivariate analyses. Results: Quantitative proteomic analysis of predominantly solid versus non-solid adenocarcinoma tissues showed 30 differentially expressed proteins consisting of 13 increased and 17 decreased proteins found in solid compared with non-solid adenocarcinoma. Four most increased proteins (MCM2, MCM4, MCM6, and SCAMP3) and two most decreased proteins (DPP4 and MYH11) were selected for immunostaining in the validation cohort of 204 patients with resected adenocarcinoma without lymph node involvement. 57 out of 204 (27.9%) patients had recurrent disease. The high expression level of MCM4 was the strongest signature for disease recurrence (HR 4.85, 95%CI 2.78-8.47, p < 0.0001) and remained significant under multivariate analyses adjusted for TNM stage, histologic subtypes, lymphovascular invasion, tumor necrosis, and adjuvant chemotherapy. Recurrence-free survival (RFS) was significantly shorter in patients with high MCM4 compared with low MCM4 (5-y RFS 50% vs 84%, p < 0.0001) and remained highly significant within stage IA (5-y RFS 69% vs 93%, p < 0.0001), or stage IB and II (5-y RFS 36% vs 69%, p = 0.001). High expression of MCM4 correlated with other poor prognosis factors including smoking (p = 0.001), stage (p = 0.003), lymphovascular invasion (p = 0.036), visceral pleural invasion (p = 0.005), tumor necrosis (p < 0.0001) and solid histology (p < 0.0001). Conclusions: High MCM4 expression serves as an important prognostic biomarker predicting recurrence in early-stage node-negative lung adenocarcinoma.
A nomogram for predicting overall survival in resected non-small cell lung cancer with chemotherapy.
Authors: Zeng Yuan , Liang Wenhua , He Jianxing
Published: May 2020

e21064

Background: Chemotherapy is very common for resected Non-Small-Cell Lung Cancer (NSCLC) patients. However, models for predicting the survival outcomes of resected NSCLC patients with chemotherapy are scarce. The aim of this study was to develop a clinical nomogram for predicting overall survival in these patients. Methods: A total of 16661 resected NSCLC with chemotherapy were cases extracted from the Surveillance, Epidemiology, and End Results (SEER) database. We identified and integrated the prognostic factors to build a nomogram.The model was subjected to bootstrap internal validation with the SEER database and external validations with 1108 patients from China. The predictive accuracy and discriminative ability were illustrated by calibration, concordance index (C-index) and risk group stratification. Results: On multivariate analysis independent factors for OS were age, sex, examined lymph node count, extent of surgery, N stage, T stage and grade which were then integrated into the nomogram. The calibration curves for probability of 1-, 3-, and 5-year OS showed excellent agreement between nomogram prediction and actual observation. The C-index of the nomogram was higher than that of AJCC 8th edition system for predicting OS (training cohort, 0.61 vs. 0.58; P < 0.01; validation cohort, 0.66 vs. 0.63, P = 0.56). The stratification into different risk groups allowed significant distinction between survival curves. Conclusions: We established a nomogram that can provide individual prediction of OS for resected NSCLC patients with chemotherapy. This practical prognostic model may help clinicians for treatment planning and to guide future studies.
Radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC): A prospective, observational study.
Authors: Berg Janna , Bengtson May-Bente , Halvorsen Ann Rita , Haugstvedt Jon Olav , Brustugun Odd Terje , Helland Aslaug
Published: May 2020

e21065

Background: RP is a clinically challenging side effect following SBRT. The reported incidence of RP varies from 2.2% to 46.8%, depending on study design and different grading systems. We evaluated the grading systems for RP and identified possible predictive tests for RP. Furthermore, we estimated the correlation between RP and dosimetric measurements from the radiation therapy. Methods: Medically inoperable patients, n = 44, with peripherally located NSCLC stage I-II, were treated with SBRT, with a total dose of 45–56 Gy in 3–8 fractions. Median age was 75 years, 43.2% were female and 60% had moderate to very severe COPD. Follow up included physical examination by pulmonologist, spirometry and single-breath lung diffusing capacity (DLCO) and CT evaluation at baseline and 1.5, 3, 6, 9 and 12 months after SBRT. Results: We constructed three groups for grading RP based on CTCAE version 5.0 and imaging changes according to EORTC (LENT-SOMA) Non-RP (asymptomatic or mild symptoms and slight imaging changes, n = 19, 43%), Asymptomatic, radiology-only RP (asymptomatic or mild symptoms, increased density imaging changes, n = 17, 39%) and Symptomatic and radiology-detected RP (moderate and severe symptoms and increased density imaging changes, n = 8, 18%). Active smokers and patients with emphysema were overrepresented in non-RP group. In the symptomatic RP group, DLCO and FEV1 dropped almost 5% 4-6 weeks after SBRT, before symptoms and imaging changes, and DLCO, FVC and FEV1 dropped significantly at 3 months (table). Development of RP was associated with critical dose-volume parameter 1000ccm and 1500ccm. Several dosimetric parameters significantly negative correlate with FVC-drop at 1 and 3 months only in symptomatic RP. Conclusions: Active smokers and patients with emphysema have less propensity of RP. Symptomatic RP is seen with a presymptomatic drop in FEV1 and DLCO occurring 4-6 weeks after SBRT. Critical dose-volume parameter is important parameters for RP. Correlation between dosimetric parameters and FVC-drop in symptomatic RP. Clinical trial information: NCT02428049 . [Table: see text]
Comparison between T1 with lymph node metastases and T3-4 without lymph node metastases in patients with non-small cell lung cancer.
Authors: Liang Naixin , Cao Lei , Cao Zhili , Bing Zhongxing , Gao Chao , Wang Yanyu , Wang Yadong , Jia Ziqi , Yang Xiaoying , Li Chengcheng , Gong Fuyu , Wang Guoqiang
Published: May 2020

e21074

Background: Patients with small tumor size but lymph node metastases (T1N1-N3, T1N1+) and patients with large tumor size but without lymph node metastases (T3-4N0, T3+N0) mainly belong to stage IIB to IIIA according to the 8th version TNM staging. However, whether the contradictory between tumor size and lymph node may influence the survival and the underlying genomic differences have not been fully studied. Methods: Whole-exome sequencing and RNA sequencing data for 1001 patients with NSCLC including 514 lung adenocarcinoma (LUAD) and 487 lung squamous cell carcinoma (LUSC) were downloaded from TCGA. The prognosis between patients with T1N1+ and T3+N0 has been investigated. The DNA sequencing data and RNA sequencing data from TCGA were used to study the underlying mechanism. Results: Patients with T3N0+ consisted of 80.2% Stage IIB and 17.4% Stage IIIA and patients with T1N1+ consist of 66.7% Stage IIB and 25.9% Stage IIIA. There were no differences in race, age, staging or neoadjuvant history between T1N1+ and T3+N0 cases. T1N1+ patients were more frequent among females (P = 0.02) and were more likely to be adenocarcinomas (P = 0.01) compared to T3+N0. Patients with T1N1+ was associated with a prolonged disease-free survival (DFS) (HR, 0.47; 95% CI, 0.28-0.79; P < 0.05) and progression-free survival (PFS) (HR, 0.31; 95% CI, 0.17-0.56; P < 0.001) than patients with T3+N0. In the multivariable cox proportional hazards regression model including stage, patients with T1N1+ still had increased PFS (HR, 0.45; 95% CI, 0.26-0.82; P = 0.009) and DFS (HR, 0.38; 95% CI, 0.16-0.95; P = 0.04) compared to T3+N0 cases. Moreover, patients with T1N2, belong to Stage IIIA according to AJCC 8th edition TNM staging, had a superior DFS (P = 0.01) and PFS (P = 0.04) compared with the patients with T3N0, who are in Stage IIB. Further investigation revealed that the tumor mutation burden was no significant difference between two groups (P > 0.05). There was no difference in genomic alterations between groups in LUSC and LUAD. GSEA analysis revealed that gene expression involved in DNA repair signaling was enriched in T1N1+ patients in LUSC and LUAD. Conclusions: Patients with T1N1+ shows a longer DFS and PFS compared with patients with T3+N0, especially T1N2 cases who belong to Stage IIIA show a better prognosis compared with T3N0 patients who are in Stage IIB, indicating the AJCC 8th edition TNM staging need to be refined. Moreover, the better prognosis in T1N1+ patients may be related with DNA repair signaling genes enrichment.
Predictive value of the Lung Immune Prognostic Index (LIPI) in locally advanced non-small-cell lung cancer (NSCLC) patients treated with concurrent chemoradiotherapy (CCRT) in the multicenter retrospective study.
Authors: Oya Yuko , Saito Go , Tamiya Akihiro , Kawachi Hayato , Fujimoto Daichi , Iwasawa Shunichiro , Suzuki Hidekazu , Niitsu Takayuki , Matsumoto Hirotaka , Miyauchi Eisaku , Yokoi Takashi , Mitsui Miho , Uenami Takeshi , Sakata Yoshihiko , Nakachi Ichiro , Okada Asuka , Hara Satoshi , Teraoka Shunsuke , Kokubo Masaki
Published: May 2020

e21076

Background: PD-L1 inhibitor, durvalumab has been approved since the PACIFIC study showed its efficacy as consolidation therapy after CCRT for locally advanced NSCLC. But predictive factor for the efficacy of CCRT on this post PACIFIC era have not been known. LIPI has been proposed as a new biomarker for the anti-PD-1 therapy of advanced NSCLC. In this study, we investigated the usefulness of LIPI as a predictive marker in multicenter cohort of patients with locally advanced NSCLC who received CCRT as initial treatment. Methods: 219 patients with available baseline LIPI were reviewed. The progression free survival (PFS) was estimated by the Kaplan-Meier method, and LIPI were calculated at baseline. Kaplan-Meier estimates of PFS and recurrence were compared using the log-rank test for trend. Multivariable analysis was conducted using the Cox and logistic regression models, respectively, adjusted for age, sex, ECOG-PS, smoking, histology, TNM stage, chemotherapy regimens, Body mass index (BMI), PD-L1 status, EGFR or ALK mutation, and baseline LIPI. Results: 62.5% (n = 137) of the patients had a good (0 factors) LIPI, while 37.5% (n = 82) had intermediate (1 factor) and poor (2 factors) LIPI respectively. In multivariable analysis, good LIPI (0 factors) were significantly associated with longer PFS (HR = 0.46, 95% CI 0.28-0.75; P < 0.01) as did ECOG-PS0 (P < 0.01), ≤stageIIIA (P < 0.01), being treated with durvalumab after CRT (P = 0.04). There were no difference in the patient characteristics between good LIPI and intermediate/poor LIPI, significantly. Higher LIPI (1 or 2 factors) were strongly prognostic factor for recurrence after CCRT in multivariate analysis (P = 0.04), along with ECOG-PS1≤ (P < 0.01), stage IIIB≤ (P < 0.01). Conclusions: The good LIPI predictive value for PFS and disease control in patients treated with CCRT was confirmed. Although a strong statistical significance, we needs to be confirmed further with longer follow-up and prospective study.
KRAS G12C mutation associated outcomes among patients with locally advanced non-small cell lung cancer.
Authors: Qian David , Behera Madhusmita , Steuer Conor Ernst , Pakkala Suchita , Carlisle Jennifer W , Owonikoko Taofeek Kunle , Fischer-Valuck Benjamin Walker , Kesarwala Aparna Hemant , Bradley Jeffrey , Curran Walter J , Ramalingam Suresh S. , Higgins Kristin Ann
Published: May 2020

e21079

Background: Recent progress in targeted therapy includes the demonstration of promising anti-tumor activity and safety of a KRAS inhibitor in patients with advanced malignancies harboring the G12C somatic mutation ( KRASG12C). KRAS mutations are present in one-third of all non-small cell lung cancers (NSCLCs), of which KRASG12C comprises about 40%. In this study we characterize the outcomes of patients with stage III NSCLC who received radiotherapy, stratified by KRASG12C status. Methods: Level 3 data for NSCLC patients were downloaded from The Cancer Genome Atlas (TCGA). Clinical and somatic mutation data were analyzed for the 118 NSCLC patients with stage III disease whose treatment included radiotherapy with or without chemotherapy. Overall survival (OS) and progression-free survival (PFS) were then compared between patients whose tumors possess versus lack KRASG12C using Cox proportional hazards regression. Results: This TCGA cohort study consists of 75 males and 43 females with stage III NSCLC (57 adenocarcinomas and 61 squamous cell carcinomas) enrolled between February 2010 and November 2014. Presence of KRASG12C was detected in 7 patients (6%) and conferred poorer OS (HR 3.14, 95% CI 1.12–8.84, P = 0.030) as well as PFS (HR 3.74, 95% CI 1.46–9.56, P = 0.0059) compared to absence of KRASG12C, with median survival of 9.0 versus 28.9 months and median time to progression of 8.5 versus 16.8 months. All 7 patients with KRASG12C had lung adenocarcinomas (ACs). Inferior survival of patients with KRASG12C persisted on subgroup analyses of AC and KRAS mutation status (Table). Conclusions: Among patients with stage III NSCLC in TCGA treated by radiotherapy, those with KRASG12C had significantly worse OS and PFS. Clinical trial of a KRAS inhibitor is a rational next step toward improving outcomes for this patient population, which has yet to be remarkably impacted by existing precision oncology approaches. [Table: see text]
APC fusions analysis in Chinese non-small cell lung cancer (NSCLC) using comprehensive NGS panel: A multicenter study.
Authors: Wang Liping , Xu Chunwei , Wang Wen xian , Zhu You-cai , Zhuang Wu , Huang Yun-jian , Fang Yong , Wang Hong , Zhang Yinbin , Wang Yafei , Chen Meifang , Li Jinluan , Cai Shangli , Fang Meiyu , Chen Gang , Lv Tangfeng , Song Yong
Published: May 2020

e21086

Background: Currently, with the advances in detection techniques, such as next generation sequencing (NGS), more and more rare or atypical APC fusions had been identified. Such as APC-MCC, the importance of Wnt signaling in the pathogenesis of lung cancer and the efficacy of EGFR-TKI treatment had been demonstrated. Methods: A multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2018. To determine the frequency of the APC fusions in NSCLC and other tumors, we analyzed data from 2743 clinical NSCLC cases, each of which had results from next-generation sequencing (NGS)-based 381 genes panel assay, analogous to the index patient. Results: Of this entire cohort, just two (0.07%) patients were identified with a APC fusion, including APC-MCC (1), APC-MRPL13 (1). The genes most frequently co-altered in patients with APC fusions were TP53 (100.00%), CCND1 (50.00%), ESR1 (50.00%), TNN (50.00%), MAP2K2 (50.00%) and POM121L12 (50.00%). Overall TMB in the APC fusions was low (median 2.16 mut/Mb). For treatments, both patients chose chemotherapy based on pemetrexed for first line, and a case example of advanced APC fusion NSCLC patients responding to anlotinib was actively being sought thru our database. Conclusions: The frequency of APC fusions in Chinese populations with NSCLC is extremely rare (0.08%). NGS can identify novel fusions and increase the list of actionable variants for patients. More patients can benefit from targeted treatment. In addition, for short-or long-term responses to TKI treatment, we can use the NGS assay to explore differential gene expression in the future.
Real-world data in limited-disease small-cell lung cancer: Results from a retrospective nationwide population-based cohort study in Korean HIRA database.
Authors: KIM Seoree , Kim In-Ho , Hong Ji Hyung , Sung Soo-Yoon , KIM Yeo Hyung , Lee Hyun Woo , Lee Jung Soo , Ko Yoon Ho
Published: May 2020

e21096

Background: Small cell lung cancer (SCLC) is a highly proliferative and rapidly growing tumor with poor prognosis, even in limited disease (LD), and a timely and accurately high intensity therapy is necessary. During the concurrent chemoradiotherapy (CCRT), etoposide with platinum (EP) regimen is recommended, however, irinotecan with cisplatin (IP) regimen is also effective. Therefore, we performed a large-scale, retrospective and nationwide cohort study to analyze the efficacy of CCRT in patients with LD-SCLC Methods: The population data were extracted from the Health Insurance Review and Assessment Service of Korea database from January 1, 2008, to November 30, 2016. Among 14,490 patients with SCLC patients who received chemotherapy, a total of 4,496 patients with LD-SCLC were analyzed. The primary objectives were to evaluate the survival outcomes of CCRT for LD-SCLC. Results: Patients who received EP-CCRT (n = 4,187) had better PFS of 11.233 months (95% confidence interval (CI) 10.900 – 11.667, P = 0.0477) and prolonged OS of 22.233 months (95% CI 21.233 – 23.333, P < 0.0001) than those who received IP-CCRT (n = 259; PFS = 9.567 months, 95% CI = 8.500 – 10.667; OS = 16.433 months, 95% CI = 14.467 – 18.333; P = 0.0477). After the failure of CCRT, we observed that dual chemotherapy (n = 925; OS = 9.133 months, 95% CI = 8.400 - 10.100) has better survival benefit (P < 0.0001) than single agent chemotherapy (n = 815; OS = 7.500 months, 95% CI, 6.933 – 8.133). IP chemotherapy demonstrated a better OS (9.567 months, 95% CI, 8.667 – 10.333 vs. 7.100 months, 95% CI, 5.100 – 10.400, P = 0.0170, respectively) than EP regimen in the platinum-resistant group; patients with PFS within 6 months after CCRT. However, in platinum sensitive group; patients who recurred after 6 months, the clinical benefit of EP regimen was superior to IP regimen (OS = 17.183 months, 95% CI, 13.033 – 25.633 vs. 6.617 months, 95% CI, 5.433 – 7.767; P < 0.0001). Cox proportional hazards regression analysis demonstrated that age, EP-CCRT, and dyslipidemia retained significant associations with OS after adjusting for all variables. Conclusions: In Korean population, concurrent thoracic radiotherapy with EP regimen had significantly favorable effects on OS and PFS. In addition, after the failure of CCRT, combination chemotherapy had clinical benefits over single agents. Among combination chemotherapy, IP combination regimen showed significantly favorable effects on OS and PFS, especially in the platinum-resistant group.
Weekly chemotherapy instead of best supportive care alone must be considered for patients of small cell lung cancer with poor performance status.
Authors: Shrivastav Gunjan , Gupta Alok , Sonthwal Neha , Singla Suhas Kirti , Mohindra Tarun , Chaturvedi Harit Kumar , Rohatgi Nitesh
Published: May 2020

e21102

Background: Many patients of Small Cell Lung Cancer (SCLC) present with advanced age & comorbidities. Although chemotherapy may benefit these patients, therapy is denied due to treatment toxicities. We studied tolerability and efficacy of weekly Etoposide with carboplatin in patients unfit for 3-weekly regimen to analyze the hypothesis if small dose weekly chemotherapy can replace the current standard of care of best supportive care (BSC) alone in patients with poor performance status (PS). Methods: We retrospectively studied consecutive patients of SCLC treated between January 2015- December 2017. Based on team’s assessment, patients received either Etoposide100 mg/m2 (Day 1,2,3) + Cisplatin25 mg/m2 (Day 1,2,3) (or Carboplatin AUC5 Day 1) q 21 days OR Etoposide100 mg/m2 + Carboplatin(AUC2)q weekly OR BSC. Responses at 6-9 weeks of therapy and toxicities were studied according to RECIST 1.1 and CTCAEv4 criteria respectively. Results: 66 patients were diagnosed with SCLC. 24 patients received 3-weekly chemotherapy regimen (Group A). Of the 42 unfit patients, 21(50 %) received weekly chemotherapy regimen (Group B). Median age was higher in Group B ( 66 vs 61 yrs ) and Co-morbidities (≥ 2)were also more in Group B, 53 vs 33 %. Furthermore, Group B had more brain metastases (38 vs 21 %) but there was equal distribution of liver metastases and SVCO (4 patients each group). Altogether Group B had worse prognostic patients. In Group A the median number of chemotherapy cycles received were 4.5 (1-8) over a median duration of 3.37 months (0.75 - 6) while in group B the median number of chemotherapy cycles were 2 (1-5) over 1.5 months (0.5 - 3.75). G-CSF was required in 22(92%) in Group A and 15(71%) in Group B. Grade 3-4 toxicity and Febrile neutropenia were seen in 11(46%) and 7(29%) patients in Group A respectively and 8(38.1%) and 7(33%) patients in Group B respectively. Progressive disease was seen in 3(13%) and 6(29%) patients in group A and B respectively. Objective response was seen in 14(59%) and 9(43%) in Group A and B respectively. Clinical benefit rate (CBR) (Objective response + Stable disease) was 75% in Group A and 57% in Group B. Among patients with brain metastasis, CBR was 60% in Group A and 50% in Group B. This was better than most patients that are not offered treatment. Conclusions: Although 3 weekly doublet remains a better regimen, weekly etoposide and platinum is a valid option for patients unfit for standard regimen with no excess toxicity. Clinical benefit is seen irrespective of poor prognostic features.
Prognostic value of SOX2 and CD8+TIL in limited stage small cell lung cancer.
Authors: Lee Jinsoo , Hong Soon Auck , Hwang Hye Won , Park Se Jun , Shin Kabsoo , Kim Joori , Lee Seung-Hwan , Lee Jieun , Kim In-Ho , Hong Sook-Hee
Published: May 2020

e21108

Background: SOX2 is a transcriptional factor that drives embryonic stem cell to neuroendocrine cells in lung development and is highly expressed in SCLC. The serum SOX2 antibody in SCLC has been known to mediate neurologic paraneoplastic syndrome. In this study, we evaluated the expression of SOX2 and CD8+ tumor infiltrating lymphocyte (TIL) in LS-SCLC from clinical tumor tissue and their impact on PFS and OS. Methods: Among the total 245 patients with SCLC treated between 2010 and 2018, 75 patients with LS-SCLC with available tumor tissue were enrolled. SOX2 and CD8+ TIL were evaluated by immunohistochemistry. High SOX2 expression was defined as above 100 of H score that was derived from multiplying intensity by the proportion of stained tumor cells. The number of CD8+TILs was counted under high magnification (x400) with four fields in intratumoral area. The cut value for high CD8+TIL was the above the median of total case. Results: 64 patients (85.4%) received etoposide/platinum and definite local therapy (radiation therapy or surgery) and 18 patients (24.0%) received surgical resection. High expression of CD8+ TIL was related to significantly longer PFS (13.9 vs. 8.0 months, P = 0.014) and tended to related to longer OS (32.1 vs. 17.4 months, P = 0.056) than low expression. High expression of SOX2 was tended to related with longer OS and PFS compared to low expression of SOX2 (median, 21.7 vs. 17.1 months, P = 0.118; 12.7 vs. 9.0 months, P = 0.110, respectively) without statistical significance. 29 patients with high CD8+TIL among 52 patients with high SOX2 had significantly longer PFS and OS compared to the other groups (median PFS 19.3 vs. 8.4 months, P = 0.002 and median OS 35.7 vs. 17.4 months, P = 0.004, respectively). Multivariate Cox regression analysis showed that combined high expression SOX2 and CD8+ TIL was an independent good prognostic factor for OS (HR = 0.449, P = 0.018) and PFS of SCLC (HR = 0.481, P = 0.021). Conclusions: In our study, high expression level of combined SOX2 and CD8+ TIL were related to longer OS and PFS, and it could be used as a prognostic biomarker for LS-SCLC. [Table: see text]
Clinical utility of a liquid biopsy diagnostic approach in lung cancer using amplicon-based next-generation sequencing in parallel with allele-specific PCR.
Authors: Choudhury Yukti , Phyo Wai Min , Lim Jing Shan , Gupta Chaitanya , Ho Yiliang , Tay Carina , Sim Yuki , Ng Wei Shuen , Pek Michelle , Tan Min-Han , Chin Tan Min , Tan Yew-Oo , Wong Seng Weng , Hsue Victor , Foo William , Sze Wing Kin , AU Siu Kei , Lam Tai Chung
Published: May 2020

e21516

Background: The utility of a liquid biopsy test for diagnosis and treatment is determined by its accuracy, molecular target coverage and timeliness to a clinically informative result. We describe our clinical experience of providing comprehensive next-generation sequencing (NGS) plasma testing for advanced lung cancer cases, including parallel testing with allele-specific PCR (AS-PCR) for rapid EGFR mutation detection. Methods: Plasma cell-free DNA (cfDNA) from advanced lung cancer patients (n = 374) underwent real-world testing with an amplicon-based NGS assay, in a CAP and ISO15189 accredited central laboratory. The assay covers 51 genes, including 8 guideline recommended biomarkers- EGFR, BRAF, MET, ALK, RET, ROS1, ERBB2 and KRAS. 168 cases (44.9%) were treatment-naïve (baseline) and 206 cases (55.1%) had received one or more lines of treatment. Parallel testing with AS-PCR for 10 specific EGFR mutations was done for 151 cases (90 baseline, 61 non-baseline). Concordance of EGFR mutation detection by the two methods, and the frequency of detection of clinically actionable (driver) mutations by NGS were assessed. Turnaround time (TAT) was calculated from sample receipt. Results: An overall concordance of 97.4% was observed for EGFR mutations between AS-PCR and NGS. When restricted to baseline cases, concordance was 100%. Among baseline cases which were concordant with AS-PCR for EGFR negativity (n = 63), driver mutations were identified in EGFR (n = 7 rarer mutations), KRAS, ERBB2, MET, NRAS, BRAF and ALK (n = 16 total) by NGS, providing an additional 37% diagnostic yield (23/63 cases). Among all baseline cases tested by NGS, a driver gene mutation was found in 64.28% of cases, including EGFR (36.9%) and KRAS mutations (11.9 %). Among non-baseline cases which were EGFR-negative by NGS and by AS-PCR, added diagnostic yield provided by NGS was 33.3% (10 of 30 cases), and included 16.7% rarer EGFR mutations. Overall, detection rate of ALK, RET, ROS1 fusions was 2.4% (n = 5, 3 and 1, respectively). Median TAT for EGFR results by AS-PCR was 1 day (range 1-2 days), while median TAT for NGS results was 10 days (range 4-13 days). Conclusions: We report excellent real-world performance of blood-based liquid biopsy testing for detecting recommended biomarkers in lung cancers, including an approach combining two orthogonal platforms for quick decision making. Clinically meaningful diagnostic yields can be obtained using a timely comprehensive NGS assay, either individually or in parallel with rapid AS-PCR testing.
Mutational profiles of lung adenocarcinoma subtypes.
Authors: Chang Shuai , Wang Yan , Wang Yi , Zhou Kun , Che Guowei
Published: May 2020

e21517

Background: Genomic profiling of lung adenocarcinoma has been studied, however, different histological subtypes were not carefully distinguished, especially in patients with mixed subtypes. Methods: Fifty-three invasive adenocarcinoma (IA) FFPE samples from lung cancer patients with detailed histological classifications were panel sequenced and analyzed. Results: Among the 53 IAs, acinar (n = 42), lepidic (n = 34) and papillary (n = 25) were most dominant subtypes and were frequently mixed with other types. Zero to 14 mutations were identified in each sample (median = 4). Thirteen of the 42 (31%) tumors containing acinar subtype harbored TP53 mutations, while none of the 11 (0%) acinar negative tumors harbor TP53 mutation; six of the 42 (14.3%) acinar positive had RBM10 mutations, while 5 of the 11 (45.4%) acinar negative had RBM10 mutations. Three of the 34 (8.8%) tumors with lepidic subtypes harbored TP53 mutations, while 10 of the 19 (52.6%) lepidic negative tumors harbored TP53 mutations; Ten of 34 (29.4%) lepidic positive tumors harbored RBM10 mutations, while 1 of the 19 (5.3%) lepidic negative tumors harbored RBM10 mutations. All papillary tumors were mixed with other subtypes. Conclusions: Different histological subtypes have different mutational features. Acinar subtypes harbor more TP53 and less RBM10 mutations than acinar negative tumors; lepidic subtypes harbor less TP53 and more RBM10 mutations than lepidic negative tumors. Lack of mucinous, micropapillary and solid subtypes requires further study to analyze their mutational signatures.
MMR deficiency of lung cancer patients.
Authors: Ming Zongjuan , Yang Shuanying , Shi Jie , Bai Jun , Wei Xuemei , Lu Qiang , Li Wei , Zhong Yujie , Yang Xia , Lyu Xin , Wei Qingbo , Gu Dejian , Chen Rongrong , Yuan Jingyan , Chen Yang
Published: May 2020

e21523

Background: DNA Mismatch repair (MMR) plays an essential role in the genetic. The main function of MMR is thought to correct post replication errors since the system could recognizes base exchanges and short DNA insertions or deletions. Somatic mutation of MMR are common detected in lung cancer, and several studies has shown that the presence of MMR mutation may be resistance to EGFR-TKI. Here we retrospectively analyzed the MMR mutation in chinese lung cancer. Methods: We retrospectively analyzed the genetic aberration in 910 Chinese lung patients. All the patients were detected by hybridization capture-based NGS 1021-gene panel. Results: Here is an interesting lung cancer case which was called EGFR T790M, TP53 and MSH2 somatic mutations without any germline mutations, and this patient showed no response to Osimertinib. We retrospectively analyzed the MMR in 910 patients and called 39 patients with MMR mutation.The percence of MLH1, MLH2, MSH3, MSH6, PMS1 and PMS2 mutations rate is as followed: 10.3% (4/39), 33.3% (13/39), 7.7% (3/39), 28.2% (11/39), 5.1% (2/39), and 15.4% (6/39) cases in PMS2 mutation. Also we found that TP53 is the most highly concurrent gene for MRR deficiency the rate is 79.5%(31/39). The rate of EGFR mutation concurrent with MMR deficiency is 27% (10/39). Conclusions: MMR deficiency was found in 4.3% chinese lung cancer and 27% of them concurrent with EGFR. [Table: see text] [Table: see text] [Table: see text]
Measuring PD-L1 mRNA expression using targeted next generation sequencing and correlation with interferon pathway activation genes in lung and colorectal cancers.
Authors: Ma Wanlong , De Dios Ivan , Antzoulatos Spiraggelos , Estella Jeffrey , Albitar Maher
Published: May 2020

e21534

Background: Expression level of PD-L1 mRNA as determined by next generation sequencing (NGS) is becoming more routinely available in cancer profiling. We explored the relevance of PD-L1 mRNA expression as detected by RNA sequencing in providing information relevant to clinical practice and compared lung cancer with colorectal cancer in activating interferon pathway. Methods: RNA was extracted from 160 non-small cell lung cancers and 53 colorectal cancers (CRC) as well as from 103 samples of various types cancers that were also analyzed for PD-L1 expression by IHC. The RNA sequencing was performed using a targeted panel of 1408 genes. IHC for PD-L1 staining was performed with the FDA-cleared diagnostic assay using the 22C3 antibody. Results: Based on comparing the number of PD-L1 IHC positive tumor cells and CD274 mRNA, significant correlation between the two methodology can be demonstrated as continuous variables (P < 0.0001) as well as when the IHC positivity is grouped as 0 to 1, 2 to 9, 10 to 49, and > = 50 (P < 0.0001). However, cancers with PD-L1 by IHC > 50% had distinctly higher levels of CD274 mRNA, while all other levels of IHC positivity showed significant overlap. Overall lung cancer showed significantly higher levels in STAT1 (P = 0.002), STAT3 (P < 0.0001), STAT4 (P = 0.005), PTPN2 (0.002) as compared with CRC. However, when only CRC cases that show PD-L1 overexpression were considered, there was no significant difference in the expression in any of these genes as compared lung cancer cases that also show PD-L1 overexpression. The only difference is that lung cancer cases with PD-L1 overexpression showed higher levels of IKBKE mRNA as compared with CRC cases with PD-L1 overexpression (P = 0.004). In addition, lung cancer overall showed higher levels of PD-L2 (P = 0.0002), PD-1 (P = 0.0002), CD8A (P < 0.0001), and CD19 (P = 0.0008), but CRC with PD-L1 overexpression showed no difference in the expression of any of these genes when compared to lung cancer cases with PD-L1 overexpression. Conclusions: While CRC shows overall significantly lower RNA levels of PD-L1, PD-L2, PD-1, CD19, CD8A and genes involved in interferon pathway, CRC cases with high expression of PD-L1 mRNA are similar to lung cancer high expressors of PD-L1. Furthermore, PD-L1 quantification using NGS testing can be used to select patient for immunotherapy and might provide valuable information on co-markers that may provide better insight to selecting patients for immunotherapy.
Clinical significance of BIM-deletion polymorphism on chemoradiotherapy in patients with non-small cell lung cancer.
Authors: Wakabayashi Yu , Masuda Takeshi , Nakashima Taku , Fujitaka Kazunori , Yamaguchi Kakuhiro , Sakamoto Shinjiro , Nishimura Yoshihumi , Horimasu Yasushi , Miyamoto Shintaro , Senoo Tadashi , Iwamoto Hiroshi , Ohshimo Shinichiro , Hamada Hironobu , Hattori Noboru
Published: May 2020

e21536

Background: The standard treatment for locally advanced non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by anti-programmed cell death-ligand 1 (PD-L1) drug therapy. BIM deletion induces apoptosis suppression and the effect of epidermal growth factor-tyrosine kinase inhibitor is reportedly attenuated in EGFR-mutated NSCLC patients with BIM deletion. This study retrospectively examined the effects of BIM deletion on CRT or PD-1 treatment in patients with NSCLC. Methods: Among patients with unresectable NSCLC at Higashi-Hiroshima Medical Center and Hiroshima University Hospital between April 1994 and April 2018, we enrolled those treated with CRT or chemotherapy using carboplatin + paclitaxel or cisplatin + vinorelbine, or PD-1 antibody treatment. Results: Of 1,224 patients with unresectable NSCLC, 88, 80, and 79 underwent CRT, chemotherapy, or PD-1 antibody treatments, respectively. Within these treatment groups, 15 (17%), 15 (19%) and 11 (14%) patients, respectively, had BIM deletion. Among patients receiving CRT, the progression-free survival and overall survival were significantly shorter in those with BIM deletion than in those without (150 vs. 254 days, p = 0.003; 429 vs. 710 days, p = 0.03). Moreover, multivariate Cox regression analysis showed BIM deletion to be an independent factor for anti-tumor effect or prognosis (hazard ratio [95% confidence interval] 2.042, [1.112–4.039], p = 0.029; 2.414, [1.063–4.984], p = 0.036). These results were not observed in the chemotherapy and PD-1 treatment groups. To confirm the association between radiation therapy effect and BIM deletion, we performed in vitro experiments using two NSCLC cell lines (A549 and EBC-1). Suppressed BIM expression using siRNA (instead of BIM deletion) in these cells showed significantly suppressed antitumor effect and apoptosis 48 hours after 30-Gy irradiation but not chemotherapy. Conclusions: We showed that BIM deletion is an independent anti-tumor effect or prognostic factor for CRT. The results also indicated that BIM deletion was associated with the effects of radiation but not chemotherapy or PD-1 antibody treatment.
Digital pathology to evaluate PD-L1 IHC scoring as a predictor of outcome with second-line avelumab treatment in patients with non-small cell lung cancer (NSCLC).
Authors: Mrowiec Thomas , Svenson Elena , Gerhold-Ay Aslihan , Wolf Corinna M , Grote Hans Juergen , Otte Marcus , Rolfe P. Alexander , Shah Parantu K. , von Heydebreck Anja , Scheuenpflug Juergen , Ruisi Mary M. , Labarta-Beceiro Violeta , Beeman Glenn , Cai Ti
Published: May 2020

e21539

Background: Assessment of programmed death ligand-1 (PD-L1) protein expression using immunohistochemistry (IHC)-based tests is currently the only approved biomarker guiding treatment of non-small cell lung cancer (NSCLC) with checkpoint inhibitors. Robust scoring guidelines and suitable cut-offs should be defined specifically for each PD-L1 IHC assay and are critical for appropriate treatment decisions. Methods: We retrospectively applied a novel digital pathology (DP) solution that mimics the conventional tumor proportion scoring (TPS) of PD-L1. The exploratory DP solution was developed and validated using samples from 340 patients enrolled in the first- and second-line (1L and 2L) NSCLC cohorts of the avelumab phase 1 JAVELIN Solid Tumor trial (NCT01772004) and 792 patients with NSCLC enrolled in the avelumab phase 3 JAVELIN Lung 200 trial (NCT02395172). Efficacy analyses were conducted for overall survival (OS) and progression-free survival (PFS) using the full analysis set with evaluable imaging data (n = 136 and n = 544, respectively). Results: Comparison of DP and conventional, semiquantitative pathologist scoring resulted in a high correlation overall (Spearman correlation coefficient, 0.86), with comparable performance for prediction of outcome to treatment with avelumab in 2L NSCLC. Consistent with conventional scoring, median OS and median PFS in avelumab-treated patients increased with higher PD-L1 expression cut-offs: in patients with ≥1%, ≥50%, and ≥80% PD-L1 expression on tumors cells, median OS was 10.0 months (95% CI: 8.6-14.3), 13.8 months (95% CI: 9.6-20.4) and 18.5 months (95% CI: 9.6-not estimable), respectively; median PFS, 3.1 months (95% CI: 2.7-4.9), 5.5 months (95% CI: 2.8-8.3) and 5.6 months (95% CI: 2.8-9.9). Conclusions: Our results demonstrate the technical feasibility, robustness, and utility of DP in scoring PD-L1 IHC in clinical trial samples, achieving comparable performance to conventional, semiquantitative pathologist scoring. Furthermore, our study supports the manual pathologist scoring algorithm (TPS scoring) in NSCLC and the selection of higher cut-offs for the PD-L1 IHC Ab clone 73-10.
Sarcopenia as a negative predictive marker for treatment with pembrolizumab as a second line in patients with metastatic non-small cell lung cancer.
Authors: Petrova Milla , Valchev Gerogi , Conev Nikolay Vladimirov , Dimitrova Eleonora , Robev Bozhil , Boneva Marsella , Pavlov Boian , Minchev Velko , Karanikolova Teodora , Valev Spartak , Gencheva Radostina , Zhbantov Georgi , Ivanova Anika , Timcheva Constanta , Donev Ivan
Published: May 2020

e21541

Background: In this multicentric retrospective study we evaluated the incidence of clinical benefit rate (CBR) and its relation to Neutrophil-Lymphocyte Ratio (NLR) and psoas major muscle area (PMMA), as well as their dynamics in patients with Non-small Cell Lung Cancer (NSCLC) treated with pembrolizumab (P) as a second line. Methods: Patients with metastatic NSCLC (n = 84) whose tumors expressed PD-L1≥1% were retrospectively analyzed between Apr 2017 and Dec 2019. All patients received platinum-containing chemotherapy (CT) as a first line treatment. Absolute neutrophil, and absolute lymphocyte count enabled calculation of NLR; NLR1 - before CT, NLR2 – before P infusion. ΔNLR was calculated. Area of PMMA was calculated at L3 position on computed tomography. CBR was defined as the proportion of patients with a partial response or stable disease for at least six months since no patients with complete response were recorded. PMMA was calculated before CT and before the P infusion; (% change rate of PMMA = ([1-PMMA before P / PMMA before CT]*100). Patients with the change rate of PMMA≥10% were considered with sarcopenia - 30 (35.7%). Results: CBR was 72.6%. There were not significant correlations between NLR, PMMA and their dynamics. Patients without clinical benefit (CB) had significantly higher values of ΔNLR (1.38±2.2) and ΔPMMA (11.2±10.7) than patients with CB - ΔNLR (0.12±1.88; p = 0.023) and ΔPPMA (8.9±13.5; p = 0.001). ROC analysis revealed that at the optimal cutoff values of all markers, ΔPMMA achieved the greatest AUC = 0.738 (95% CI, 0.77-0.93) and could distinguish between patients with or without CB with sensitivity of 77.3% and specificity of 83.6%. Sarcopenic patients had significantly shorter mean progression-free survival (PFS) – 6.5 months (95%, CI 5.1-8.1) than the rest – 20.8 months (95%, CI 16.7-24.1). Moreover in the multivariable analysis, ΔNLR (HR 1.19, 95% CI 1.05-1.38, p = 0.01) and ΔPPMA ≥10 % (HR 5.4, 95% CI 2.82-10.19, p < 0.001) were found to be independent predictive factors for shorter PFS. Conclusions: Our data suggests that ΔPMMA and ΔNLR are potential predictive markers, which may identify patients appropriate for immunotherapy as a second line treatment.
High neutrophil to lymphocyte ratio as a predictor for hyperprogressive disease in patients with metastatic non-small cell lung cancer treated with pembrolizumab as a second line.
Authors: Petrova Milla , Eneva Mariyana , Arabadjiev Jeliazko Iliev , Conev Nikolay Vladimirov , Dimitrova Eleonora , Koynov Krassimir Dimitrov , Karanikolova Teodora , Valev Spartak , Gencheva Radostina , Zhbantov Georgi , Ivanova Anika , Sarbianova Iva , Penkova Polya , Timcheva Konstanta , Donev Ivan
Published: May 2020

e21546

Background: In this study we evaluated the incidence of early non-responders (which are potential hyper-progressors (HP)) and its relation to Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR) as well as their dynamics in patients with Non-small Cell Lung Cancer (NSCLC) treated with pembrolizumab (P) as a second line. Methods: Patients with metastatic NSCLC (n=119) whose tumors expressed PD-L1≥1% were retrospectively analyzed between Apr 2017 and Oct 2019. All patients received platinum-containing chemotherapy (CT) as a first line treatment. Hematological parameters of interest were absolute neutrophil (ANC), absolute lymphocyte (ALC) and platelet (APC) counts, enabling calculation of NLR (ANC/ALC) and PLR (APC/ALC). NLR1 and PLR1 were calculated before CT, NLR2 and PLR 2 – before the first P infusion. ΔNLR (NLR2-NLR1) and ΔPLR (PLR2-PLR1) were calculated. The tumor response was assessed according to the RECIST (version 1.1) at every 3 months. Early progressors (EP) were defined as non-responders at the first computed tomography scan evaluation of the CT. As HP on P were considered patients with time to progression ≤ 3 months, clinical deterioration and appearance of ≥2 new lesions in organ already involved or spread to a new organ. Results: Twelve (10.1%) patients in the CT group were EP. Fourteen (11.8%) patients in the immunotherapy group were assessed as HP. Four patients (3.4%) did not respond either to CT or to P and had clinical aggravation. HP had significantly higher NLR2 (9.1±1.9 vs 4.8±3.2, p<0.001), PLR2 (400±173.8 vs 214.7±117.3, p<0.001), ΔNLR (2.3±1.9 vs 0.3±2.0, p=0.001), ΔPLR (107.9±167.3 vs 0.6±94.9, p=0.012) than the rest of the patients. ROC analysis revealed that at the optimal cutoff values of all markers, NLR2 achieved the greatest AUC=0.855 (95% CI, 0.77-0.93) and could distinguish between patients with or without hyperprogressive disease (HPD) with sensitivity of 85.7% and specificity of 72.4%. HP had significantly shorter mean OS - 12.5 months (95%, CI 10.9-14.1) than the rest – 32.2 months (95%, CI 28.4-36.1). Patients who did not respond either to CT or to P had significantly shorter mean OS – 9.2 months (95%, CI 6.6-11.8) than the rest – 29.8 months (95%, CI 26.4-33.4). NLR was found to be an independent predictive factor for HPD, HR=1.22 (95% CI,1.11-1.35; p<0.001). Conclusions: Our data suggest that the incidence of intrinsic aggressive disease phenotype, irrespective of treatment, is low. NLR is a novel predictive marker for HPD.
Concordance of next-generation sequencing between tissue and liquid biopsies in non-small cell lung cancer.
Authors: Basher Fahmin , Saravia Diana , Fanfan Dino , Cotta Jared Addison , Lopes Gilberto
Published: May 2020

e21547

Background: While genetic profiling has become standard of care for patients diagnosed with non-small cell lung cancer (NSCLC), next-generation sequencing (NGS) provides a wealth of information about targetable mutations. Advances in genetic testing have led to sequencing platforms that utilize tissue itself or extracellular circulating tumor DNA in the blood, known as a “liquid biopsy.” Methods: We identified 55 patients with NSCLC who had undergone both tissue and liquid biopsy, using Foundation One and Guardant 360 at the University of Miami / Sylvester Comprehensive Cancer Center between January 2016 and December 2018, and performed retrospective analysis to determine patient characteristics as well concordance between different NGS platforms. Results: In our patient population, 34% of patients had never smoked prior to diagnosis, while 22% had more than a 30 pack-year smoking history. 64% of patients had no treatment prior to initial NGS. 40% of patients had both testing done essentially simultaneously, while 60% of patients had one test done after disease progression. Of these patients, therapy was changed as a result in 73%. Median number of days between tests was 21 days, with 56% of testing done within 90 days of the previous testing. Nine patients had an additional Foundation One tissue NGS performed. Concordance across all genes tested in both platforms was 98 ± 0.2%. Concordance with consideration of genetic alterations detected in both assays was 24.5 ± 3.0%. The median number of gene alterations determined by Foundation One testing was 4 (range 1-9), while the median for gene alterations detected by Guardant 360 was 3 (range 1-13). The median number of variants of unknown significance (VUS) was 10 (range 5-25). Conclusions: Our analysis indicates a role for both tissue-based and circulating tumor DNA-based NGS for determination of targetable mutations and thus appropriate treatment regimens. Low levels of concordance are potentially related to post-treatment changes in the tumor genetic profile as well as evolution in the testing itself.