bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic landscape and PD-L1 expression of Chinese patients with small cell lung cancer.
Authors: Chen Meifang , Zhang Ding , Wang Guoqiang , Wang Bijiong
Published: May 2020

e21099

Background: Small cell lung cancer (SCLC) is a highly aggressive carcinoma of the lung. Whereas, precise treatment options for SCLC are limited. Genomic profiling would be essential to understand drug resistance related mechanism. So far, little is known about an in-depth molecular characterization for SCLC in Chinese patients. Here we described the mutational landscape and programmed cell death-1 (PD-L1) expression profile in Chinese patients with SCLC by next-generation sequencing (NGS) assay. Methods: Chinese patients with SCLC were included in this study. Genomic profiling of DNA was performed on formalin-fixed paraffin-embedded tumor samples and matched blood through a NGS with 381 cancer-related genes panel. PD-L1 expression status of tumor tissue was determined by immunohistochemistry. Results: In total, 115 patients with SCLC were included in the present study. We identified 2,948 mutations, spanning 434 genes, with TP53, RB1 and LRP1B being the most frequently mutated genes, occurring in 109(94.78%), 88(76.52%) and 48(41.74%) of SCLC patients, respectively. For somatic single nucleotide variant (SNV), TP53 (108/115, 93.91%), RB1 (82/115, 71.30%) and LRP1B (43/115, 37.39%) were frequently mutated, which exhibited the similar mutation frequencies with TCGA database. To be noted, 79 (68.70%) SCLC patients harbored both RB1 and TP53 mutations, which was comparable with TCGA data (84/110, 76.36%). Germline SNV spectrum varied significantly compare with somatic SNV. BLM, MSH2 and VEGFA were the most frequently germline mutated genes. In our dataset, the tumor mutation burden (TMB) of 108 patients, PD-L1 expression status of 95 patients and microsatellite stabilities/instabilities (MSS/MSI) status of 112 patients were also analyzed. The median TMB was 10.61/MB. The positive rate of PD-L1 expression was 12.63%. All patients were MSS. Conclusions: Our study revealed the genetic landscape and PD-L1 expression of SCLC. The data may provide the support on immunotherapy and targeted therapy research.
First-line apatinib plus chemotherapy in extensive-stage small-cell lung cancer.
Authors: Shi Jian , Liu Jiayin , Duan Xiaoyang , Huang Guanglei , Wang Lixing , Zhao Yan
Published: May 2020

e21104

Background: Angiogenesis plays a critical role in the growth, progression, and metastasis of numerous solid tumor types. Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), which is inhibits tumor angiogenesis. Etoposide plus cisplatin is a standard chemotherapy regimen for Extensive-Stage Small-Cell Lung Cancer (SCLC). Combining apatinib with chemotherapy may have a synergistic effect and improve efficacy. Methods: Eligible patients were adults with histologically or cytologically confirmed extensive-stage small-cell lung cancer, excluded patients with symptomatic brain metastases. Measurable extensive-stage small-cell lung cancer according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Eligible patients were received six 21-day cycles of apatinib (250mg, orally daily) and chemotherapy (etoposide:100 mg/m2, ivgtt d1-3 of each cycle; cisplatin: 80 mg/m2, ivgtt d1 of each cycle), followed by local radiotherapy, apatinib (250mg, orally daily) maintenance therapy. For patients who have received treatment less than 6 cycles have disease progression, change the chemotherapy regimen combined with local radiotherapy. Primary endpoint: 6-month ORR. Secondary endpoints: 6-month DCR, PFS, safety. Results: We enrolled 40 patients between November 15, 2017 and April 18, 2019. Median age was 56 (range 28-67), 92.5% had an ECOG PS of 0. At the data cutoff (December 31, 2019), 27 patients were evaluated. In 27 patients who received apatinib for 4-26 months, with average of 10.6 months. The 6-month ORR was 63%, DCR was 85% [17 PR, 6 SD]. 9 patients (33.3%) achieved PFS, of which 8 patients progressed within 9 months and 1 patient progressed within 22 months. Patients who progressed within 6 months, the average duration of apatinib was 5.1 months. During the therapy, adverse events (AEs) were mostly Common grade 1-2 related AE, hypertension (37%), hand-foot syndrome (3.7%), and Hepatic Insufficiency (7.4%). Conclusions: Our study suggests that oral apatinib plus chemotherapy should be considered an active and safe treatment in patients with first-line treatment of extensive-stage small-cell lung cancer.
Atezolizumab and platinum-based chemotherapy in extensive-stage small cell lung cancer: A single center experience.
Authors: JAKOPOVIC MARKO , Bitar Lela , Krpina Kristina , Seiwerth Fran , Marusic Ante , Plestina Sanja , Kukulj Suzana , Roglic Mihovil , Korsic Marta , Badovinac Sonja , Samarzija Miroslav
Published: May 2020

e21110

Background: In extensive stage small-cell lung cancer (ES-SCLC) immune check-point inhibitors, atezolizumab and durvalumab, when combined with chemotherapy in the first-line setting show better efficacy than chemotherapy alone with safety profile similar as the adverse events of individual agents. Methods: We administered atezolizumab, etoposide and platinum, either carboplatin or cisplatin, in the first-line treatment in 24 newly diagnosed patients with ES-SCLC. Patients were treated until disease progression or unacceptable toxicity. Results: Out of 24 treated patients 13 were males and 11 were females, median age 61 (ranging from 44 to 80). Majority of patients were ECOG 1. Median number of atezolizumab doses was 8 (ranging from 2 to 11). We observed median progression free survival of 6 months (95%CI 4,28-7,72), while median overall survival was not reached. 10 patients (41%) are still undergoing treatment and 9 patients (37%) have died. Immune-related adverse events occurred in 6 patients (25%). Four patients developed pneumonitis (all of them CTCAE grade 2), two patients colitis (CTCAE grade 2 and 3) and one patient rash, CTCAE grade 3. Median treatment pause was 5 weeks (ranging from 3 to 12 weeks). There were no treatment discontinuations due to adverse events nor treatment related deaths. Conclusions: Atezolizumab combined with chemotherapy in ES-SCLC showed good tolerability and effectiveness in real world setting. Our data are consistent with published clinical trial data. There was no new safety signal in our patient cohort. Limitations of our report are small sample size and short follow-up time.
Effect of personalized approach to therapy in non-small cell lung cancer (NSCLC) with liver metastasis with immunotherapy on outcomes.
Authors: Badin Kristine , Waseem Bushra , Ullah Asad , Abdel Karim Nagla Fawzy , Eldessouki Ihab , Guttery Boyd
Published: May 2020

e21504

Background: Patients with NSCLC with liver metastasis tend to have significantly reduced overall survival (OS) compared to NSCLC with metastasis to other sites. We aimed looking at the patients with lung cancer at our institution over a five year period and assess the outcome of NSCLC with liver metastasis based on different treatment modalities. Methods: This is a retrospective study of patients with NSCLC and liver metastasis over the past five years. Patient data was securely collected and stratified based on demographics, histology, driver mutation analysis, date of diagnosis, place of metastasis, date of treatment, types of treatment received, and date of death, as applicable. Results: Eight of 132 patients had liver metastasis. Out of which one had SCLC and was treated with carboplatin-etoposide-atezolizumab with OS of 17 months. Remaining seven were NSCLC where five patients had adenocarcinoma and 2 had squamous histology. Pembrolizumab was part of treatment for all 4 patients with adenocarcinoma. 5th patient was treated with chemotherapy and had OS of 2 months. Female to male ratio 3:2 for adenocarcinoma and 0:2 for squamous histology with equal ethnic distribution. Two patients had squamous histology, both males and had average OS of 4.5 months. Conclusions: Patients with liver metastasis regardless of the histology, have short overall survival. However it was observed that such patients when treated with immunotherapy as part of their treatment modality do much better compared to those who did not. Specifically immunotherapy benefits are more pronounced in patients with adenocarcinoma histology compared to squamous. However further studies are indicated to evaluate personalized approach to therapy in NSCLC with liver metastasis. Our study was limited based on our limited number of patients.
Prospective study for usefulness of circulating-free DNA on prediction of third generation EGFR tyrosine kinase inhibitors.
Authors: Yoshida Hironori , Nakashima Chiho , Matsumoto Naohisa , Iwanaga Kentaro , Ebi Noriyuki , Nishiyama Akihiro , Yatera Kazuhiro , Fukuda Minoru , Ushijima Sunao , Umeguchi Hitomi , Harada Daijiro , Kuyama Shoichi , Kashiwabara Kosuke , Suetsugu Takayuki , Fujimoto Nobukazu , Nakatomi Katsumi , Tanaka Fumihiro , Uramoto Hidetaka , Yoshii Chiharu , Sueoka-Aragane Naoko
Published: May 2020

e21510

Background: Most non-small lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations develop resistance when exposed to EGFR-tyrosine kinase inhibitors (TKIs). T790M develops in about half of patients treated with TKI and can be detected by tumor tissue and cfDNA hotspot tests. However, co-occurring mutations at other loci may impact efficacy. We conducted a prospective, multi-center, observational study to assess the detection rates and predictive values of plasma-based EGFR T790M detection methods for Japanese NSCLC patients treated with osimertinib. Methods: NSCLC patients with tumor EGFR mutations and disease progression after treatment with 1st- or 2nd-generation EGFR-TKI were enrolled. Plasma was collected at the time of clinical disease progression, before osimertinib treatment. The collected plasma was tested for EGFR T90M by in-house plasma MBP-QP and ddPCR assays and compared to clinically tested cobas (Roche) results (including tissue, plasma). The primary endpoint was to demonstrate comparability of our MBP-QP system to cobas using plasma-based EGFR T790M detection to predict the therapeuitic effect of osimertinib via objective response rate (ORR) and disease control rate (DCR). As an exploratory analysis, we used Guardant360 to retrospectively test available banked plasma samples collected describe time points. Results: From Feb 2017 to Jan 2019, 145 patients enrolled. T790M was detected by cobas in 57 cases (44 tissue, 16 plasma, 3 both). ORR and DCR in plasma cobas-positive cases were 62.5% and 81.3%, respectively. MBP-QP found T790M in 9 patients with ORR and DCR 66.7% and 77.8%. ddPCR found 17 cases with ORR and DCR 70.6% and 82.4%. ORR was not correlated to AF. In plasma samples from 54 patients, Guardant360 detected T790M in 57%. Co-occurring alterations such as amplification or minor mutations in EGFR or other genes such as TP53 did not impact ORR, but in the group with poor response to osimertinib, the number of detected gene alterations tended to be large. Two patients with small cell carcinoma transformation had RB1 mutations and MYC amplification. Conclusions: Regardless of the test system, the detection of T790M could predict a good therapeutic effect of osimertinib, but there was no difference in response to osimertinib depending on EGFR T790M AF. Compared to single-gene assessment of EGFR, NGS of cfDNA may be useful for guiding treatment decisions for patients with TKI-resistant NSCLC. Clinical trial information: UMIN000025930.
Molecular characterization of patients with advanced lung adenocarcinoma at diagnosis with next generation sequencing by liquid biopsy in the Mexican population.
Authors: Martínez-Herrera José Fabián , Martinez-Barrera Luis , Rodriguez Cid Jeronimo Rafael Rafael , Sánchez-Ríos Carla Paola , Sanchez-Prieto Mario Alberto , Flores-Mariñelarena Rodrigo Rodrigo , Andrade Moreno Raul Alejandro , Saenz-Frias Julia Angelina , Alatorre-Alexander Jorge
Published: May 2020

e21511

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Tumor biopsy represents the standard for molecular diagnosis, nevertheless it is not always feasible to obtain. Liquid Biopsy (LB) may offer an alternative in the first line setting. Methods: Retrospective review of case files and next generation sequencing report (NGS) from LB from patients in a Validation Trial, performed from January 2018 to September 2019. We present the molecular alterations and clinical characteristics of the population. Results: 147 records and LB reports of patients 18 years and older with metastatic lung adenocarcinoma without prior treatment were included. 40% of the population had been selected based on a commercial local PCR test for EGFR (Idylla). 49% of them were female with Mean age of 60.9 ± 12.7. 56% had a history of smoking with an average packs/year of 20.5 (1-156) and 39% had exposure to wood smoke, 92% had an ECOG 0-1. 65 % of the Patients were diagnosed in Clinical Stage (8th Edition) IVA and 22% in IVB. 13% had SNC metastasis. The LB detected genomic alterations in 85.5% of the cases. 78% represent pathogenic mutations and 7.5% variants of uncertain significance (VUS).14.5% of the biopsies could not detect any ctDNA. The most frequent aberrations reported were TP53 in 51.7%, KRAS 16%, EGFR 16%, ALK 9%, PIK3CA 4%, RET 4%, BRAF 3%, BRCA 3, and HER2 3%. In addition, 20% had bTMB ≥10. Only 20% of the patients could receive a targeted therapy or immunotherapy of the potential ≈50%. Most cases had co-mutations (1-6 x case). Looking for factors associated with the presence of bTMB by a logistic regression model, it was possible to identify the presence of CNS metastases and smoking as identified with an OR of 3,688 (p = 0. 0.042) and 3.952 (p = 0. 024) respectively. Conclusions: It is feasible to have tumor molecular analysis through liquid biopsy in most cases, with genetic alterations previously reported in tumor tissue in the first line setting. [Table: see text]
Analysis of canonical and noncanonical splicing site mutation of MET that causes exon 14 skipping.
Authors: Yu Yongfeng , Chen Rongrong , Zhao Jun , Yi Xin , Lu Shun
Published: May 2020

e21513

Background: The hepatocyte growth factor receptor gene ( MET) exon 14 skipping ( METex14) has been wildly accepted as a driver alteration in lung cancer targetable by tyrosine kinase inhibitors (TKIs) such as crizotinib. While it is easy to interpret canonical splicing site mutations, it is more controversial to interpret noncanonical splicing site mutations. Methods: Hybrid capture–based next generation sequencing of 59-1021 genes including MET was performed at the request of individual treating physicians. The mutation profiling of MET were retrospectively analyzed. Results: Of 3500 lung cancers profiled by comprehensive genomic profiling, 211 harbored MET single nucleotide mutation (SNV), or small insertion/deletion (InDel). Among which 66 cases were predicted to have METex14. Forty-two (62.1%) cases harbored mutations affecting the splicing donor site, while 24 harbored mutations affecting the splicing acceptor site. Thirty-four of the 42 cases affecting the splicing donor site had mutations in the canonical splicing site, including 3 cases harbored MET c.3028G > A/T/C mutation, 14 cases harbored c.3028+1G > A/T/C, 10 cases harbored c.3028+2T > A/C/G, 8 cases harbored deletion of the whole canonical splicing site. Interestingly, all the seven cases affecting the noncanonical splicing donor site were c.3028+3A > G/T mutation. On the contrary, all the 24 mutations affecting the splicing acceptor site were deletion with/without insertion, with 12 affecting the canonical site and 12 the noncanonical site. We speculated that the polypyrimidine tract around the splicing acceptor site making it more susceptible to deletion/insertion, and thus single nucleotide variant less common. Conclusions: At the 5’ end of the exon 14 of MET, most of the genome alterations are deletions with/without insertions affecting the canonical and noncanonical splicing acceptor site. At the 3’ end, they are mostly point mutations affecting the splice donor site. The noncanonical splicing donor site c.3028+3A plays crucial role in the splicing of exon 14 in MET.
Specific organ metastases and survival of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutation.
Authors: Shi Tiantian , Wang Long , Fan Zhisong , Feng Li , Han Jing , Su Yu , Zhou Xinliang , Zuo Jing , Liu Fengling , Jiang Da , Xu Xiaoli , Wang Yudong
Published: May 2020

e21527

Background: The retrospective study was performed to evaluate the clinicopathological characteristics and survival associated with distant metastasis from advanced NSCLC with EGFR mutation. Methods: The records of metastasis NSCLC patients with EGFR mutation at the time of diagnosis between 2012 and 2018 were reviewed. The Kaplan-Meier method was used to assess survival curves and the log-rank test was used in the univariate analysis. The multivariate survival analysis were performed using the Cox proportional hazards model to investigate the effects of clinicopathological factors on survival. All the statistical analyses were performed using SPSS 23.0 statistical software and a statistically significant difference was determined as P < 0.05. Results: A total of 258 NSCLC patients with EGFR mutation were enrolled in this study, including 146 cases of female (56.6%), 241 cases of adenocarcinoma (93.4%) and 212 cases of non-smokers (82.2%). Among these patients, 65(25.2%), 111(43.0%), 22(8.5%), 107 (41.5%), 11(4.3%), 87 (33.7%), 65 (25.2%) had brain, bone, liver, lung, adrenal gland, pleural metastasis and extrathoracic lymph node metastases, respectively. The median OS of total patients was 32.9 months (95% CI: 29.8-36.0). In the univariate analysis, patients with metastases to the bone (p = 0.001), liver (p = 0.012), extrathoracic lymph node(p = 0.006), and pleural(p = 0.008) exhibited a poorer survival compared to those without metastases to these regions. Abdominal metastases (p = 0.005) and extremity metastases (p = 0.002) were statistically independent prognostic factors. Association between metastatic region and the response to TKI treatment, liver metastases (p = 0.033), extrathoracic lymph node metastases (p = 0.000) and bone metastases (p = 0.009) were correlated with the poor response of TKI treatment, and the abdominal metastasis ( p= 0.029) and extremity metastases ( p= 0.016) were correlated with the poor response of TKI treatment. Conclusions: Bone metastases, liver metastases, extrathoracic lymph node metastases and pleural metastases were independent prognostic factors of NSCLC patients with EGFR mutation. Liver metastases, extrathoracic lymph node metastases, and bone metastases were correlated with the poor response of TKI treatment.
Bevacizumab biosimilar and reference bevacizumab in subjects with stage IIIB/IV no squamous non-small cell lung cancer (NSCLC) (STELLA study): Results for the primary endpoint in a confirmatory, double-blind, randomized, controlled study.
Authors: Millan Susana , Trukhin Dmytro , Kolesnik Oleksii , Poddubskaya Elena , Zoran Andric , Bondarenko Igor , Shevnia Serhii , Bullo Felicitas , Sarnago Cristina
Published: May 2020

e21542

Background: MB02 is a proposed biosimilar of the reference bevacizumab. A multinational, double-blind, randomized, parallel group clinical study (STELLA) is undergoing to confirm clinical similarity between MB02 and bevacizumab in patients with stage IIIB/IV no squamous NSCLC. Methods: Subjects were randomized 1:1 to MB02 or bevacizumab (15 mg/kg) plus chemotherapy (paclitaxel [P] 200 mg/m2 and carboplatin [C] AUC6) on Day 1 of every 3-week cycle for 6 cycles (Week 18) followed by MB02/bevacizumab in blinded monotherapy until disease progression, treatment intolerance, death, patient withdrawal or end of study (Week 52). As primary study endpoint, the efficacy by means of the objective response rate (ORR) evaluated by an independent radiological committee (IRC) was compared between arms at Week 18. Secondary endpoints were Progression Free Survival (PFS) and Overall Survival (OS), safety and immunogenicity (assessed at 18 and 52 weeks). Results: 627 patients were randomized: MB02 (n = 315) and bevacizumab (n = 312). Demographic and baseline characteristics were well balanced between arms. The ORR results were comparable for subjects receiving MB02 or bevacizumab plus P/C. A Risk Ratio (RR) of 1.013 (90% CI: -0.037% to 0.059) and a Risk Difference (RD) of 0.011 (90% CI: -0.037% to 0.059), were within the similarity margin predefined by FDA (0.73, 1.36) and EMA (-12%, +12%) respectively. This ORR assessed by IRC was consistent with the investigator assessment criteria. There was no significant difference between arms for secondary efficacy endpoints (PFS/OS) at week 18. Up to primary endpoint cut-off point, the safety assessment showed no significant differences between MB02 and bevacizumab arms (including the immunogenicity assessment) in terms of nature, frequency and severity of the adverse events (AE), being anaemia and hypertension the most common IMP-related AEs, with a RD between treatment groups < 5%. New signals or observable trends were no reported for MB02-treated subjects. Additional information on the secondary endpoints will be available at week 52 (end of monotherapy period). Conclusions: The statistical analysis executed for ORRs confirm the equivalence of MB02 and bevacizumab, supporting the clinical activity of MB02 treatment. MB02 was well tolerated with manageable AEs in patients with Stage IIIB/IV NSCLC. Clinical trial information: NCT03296163.
Assessment of quality and clinical similarity (pharmacokinetic and safety) of HD204, a biosimilar of bevacizumab.
Authors: Hii Jocelyn , Demarchi Martin , Coliat Pierre , Kim Michael J , Chan Kuo Wei , Feyaerts Peggy , Ang Felicia , Schott Roland , Barthelemy Philippe , Benabdelghani Meher , Deforce Filip , Derde Marie_Paule , Pivot Xavier , Park Lisa Soyeon
Published: May 2020

e21556

Background: Prestige Biopharma Pte Ltd is developing HD204, a biosimilar candidate of Bevacizumab (Avastin). Bevacizumab has been approved in the treatment of a variety of metastatic tumours. Bevacizumab, a recombinant humanized monoclonal antibody block angiogenesis which is required for cancer progression by preventing binding of soluble vascular endothelial growth factor (VEGF) to VEGF receptors. Due to heterogeneity nature of antibody therapeutic, the impact on quality of HD204 on safety and pharmacokinetic (PK) was reaffirmed through clinical study to establish clinical similarity between HD204 and Avastin. Methods: Quality attributes identified to influence PK and safety established through comprehensive analytical characterization was used to correlate any potential differences (structural or biological) between the two compounds if any, could result in any clinical meaningful differences in safety and PK in the clinical settings. The PK and safety equivalence of HD204 relative to Avastin was demonstrated in a randomized, single-blind, single-dose, three-arm and parallel-group study clinical Phase I (SAMSON). A total of 120 healthy male subjects randomized 1:1:1 were to receive 1 mg/kg intravenous infusion of either HD204, EU- or US-Avastin. Various PK parameters, safety assessments not limiting to adverse events (AE) and measurement of antidrug antibodies (ADA) and neutralizing antibodies (NAb) were evaluated. Results: The pairwise comparisons of Exposure (AUC0-inf and AUC0-last), maximal concentration (Cmax) established equivalence between the 3 arms. All other PK parameters including half-life, clearance and volume of distribution were comparable between HD204 and Avastin treatment groups. Treatment related TEAEs reported for each group were 25.0%, 30.0% and 25.6% respectively and comparable. There were no treatment-emergent SAEs. Furthermore, none of the subjects treated with HD204 was ADA positive. Conclusions: HD204 demonstrated equivalent PK and safety profile to both US-Avastin and EU-Avastin at 1mg/kg administered as a 90-minute IV infusion to healthy male subjects. A prospective clinical study aimed to demonstrate equivalence in terms of efficacy, PK and safety is currently ongoing. Clinical trial information: 2017-005174-19.
Real-world mutational profiling of Chinese non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) uncommon mutations acquired resistant to icotinib using next generation sequencing: A multicenter study.
Authors: Wang Wen xian , Xu Chunwei , Lei Lei , Zhu You-cai , Li Jinluan , Chen Huafei , Fang Yong , Wang Hong , Zhuang Wu , Fang Meiyu , Zhang Yinbin , Wang Liping , Zhang Huibao , Zhou Ying , Zheng Yu , Hu Xugang , Jiang Weiping , Chen Gang , Lv Tangfeng , Song Yong
Published: May 2020

e21557

Background: Just like classical EGFR mutations, EGFR uncommon mutations non-small cell lung cancer (NSCLC) will still have acquired resistant problem to icotinib. The mechanism of icotinib resistance in such uncommon EGFR mutant patients has also risen to be a difficult question in lung cancer research. In order to explore the resistance mechanism in EGFR uncommon mutant NSCLC patients treated by icotinib, it is necessary to first identify the resistant gene profiles and clinic-pathologic characteristics of those patients. As far as we know that there is no large cohort of EGFR uncommon mutant NSCLC study in evaluating the efficacy and resistant genomic profiling of icotinib. Methods: We screened 3279 patients with NSCLC for EGFR uncommon mutations. Among them, 106 patients received icotinib treatment, and a total of 69 patients with stage IIIb-IV EGFR uncommon mutations NSCLC were undergoing tumor biopsies or blood withdrawing by the time of primary or acquiring to icotinib, in including formalin-fixed paraffin-embedded (FFPE) samples, serum samples and serous effusions. We used targeted next-generation sequencing to detect genes status of patients. Results: Among 69 patients treated with icotinib, 69.57% (48/69) developed acquired resistance, and 30.43% (21/69) had primary resistance. Using the specimens at the baseline, there were 39(81.25%) patients with EGFR T790M (including 7 patients with EGFR T790M, 32 patients with EGFR T790M plus EGFR amplification), 3(36.25%) patients with EGFR amplification, 1(2.08%) patient with BRAF mutation, 1(2.08%) patient with PIK3CA mutation, 1(2.08%) patient with CTNNB1 mutation, 1(2.08%) patient with ALK fusion, 1(2.08%) patient with ROS1 fusion, and 1(2.08%) patient with unknown status. Conclusions: EGFR T790M, EGFR amplification, BRAF mutation, PI3K-AKT-mTOR signaling pathway (PIK3CA mutations), CTNNB1 mutation, ALK fusion or ROS1 fusion might contribute to molecular mechanisms of acquired resistance to icotinib in EGFR uncommon mutations NSCLC. Our study uncovered EGFR uncommon mutational profiles of NSCLC patients with icotinib resistance with potential therapeutic implications.
Does CNS metastases reduce systemic therapy lines for NSCLC patients with EGFR mutation?
Authors: Giffoni Danilo , Romero Maria Luisa , Doherty Mark
Published: May 2020

e21558

Background: The latest generation tyrosine kinase inhibitor (TKI), Osimertinib, targets the epidermal growth factor receptor (EGFR) despite the T790M mutation status in non-small-cell lung cancer (NSCLC). In cases where there is a detected EGFR mutation on the exon 19-deletion and on the exon 21-L858R in the NSCLC population, studies have demonstrated that Osimertinib has a positive benefit in overall survival and delayed progression of central nervous system (CNS) metastases. Methods: From January 2010 to December 2018, 56 patients with the metastatic NSCLC-EGFR mutation, treated with Osimertinib 80 mg once daily, were included in this analysis. Retrospective data was extracted through the internal administrative databases located at Sunnybrook Hospital. All patients had EGFR mutation positivity by cytology, plasma or tissue sampling. The primary endpoint was to evaluate whether NSCLC patients who were exposed to Osimertinib and had brain metastases underwent fewer systemic therapy lines as compared to those who did not have metastases involving the brain. Results: Eligible patients were analyzed and the median age at the initial diagnosis was 65 years old; 50% (n = 28) of the patients had brain metastases. The median of systemic treatment lines for patients without CNS metastasis was two and for those who have metastases to the brain was three. 82,2% of this cohort received Osimertinib in 2nd line, after development of acquired resistance to first or second TKI generation. Conclusions: Results from this study did not demonstrate that EGFR mutated, NSCLC patients with CNS metastases received less systemic therapy lines to those without metastases involving the brain. A larger cohort for further investigation is warranted.
Musashi 2 (MSI2) expression as an independent prognostic biomarker in non-small cell lung cancer (NSCLC).
Authors: Deneka Alexander , Kharin Leonid , Karnaukhov Nikolay S. , Voloshin Mark , Ayrapetova Tamara G. , Ratner Elena , Sabirov Alexey , Topchu Yulia , Mazitova Alexandra , Abramova Zinaida , Yugai Veronika , Frantsiyants Elena M. , Kit Oleg Ivanovich , Boumber Yanis
Published: May 2020

e21583

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the world, and metastasis is the most common cause of death in lung cancer patients. Musashi-2 (MSI2) is a member of RNA-binding protein family and regulates mRNA translation of numerous intracellular targets, and influences multiple biological processes, including maintenance of stem cell identity. Previously we reported that MSI2 is upregulated in the metastasis-competent NSCLC murine and human cell lines, drives NSCLC metastasis, and is progressively elevated in lung cancer patient samples. This study assessed MSI2 as potential clinical biomarker in NSCLC. Methods: The current study included 40 patients with NSCLC, of whom 15 presented with stage II and III respectively (37,5% each), and 10 patients (25%) had stage IV. All patients received treatment in accordance with the NCCN guidelines, and did not participate in clinical trials. All patient samples were obtained before treatment started. We used immunohistochemical (IHC) approach to measure MSI2 expression on the protein level in matching specimens of normal versus tumor tissues, and primary tumor vs. metastasis, followed by correlative analysis in relation to clinical outcomes. In parallel, clinical correlative analysis of MSI2 mRNA expression was performed in silico using publicly available datasets (TCGA/ICGC) as of January 2020. Results: MSI2 protein expression in patient samples was significantly elevated in NSCLC primary tumors and metastatic sites versus normal tissue (p = 0.03). MSI2 elevated expression positively correlated with a decreased progression free survival (PFS) (p = 0.026) at all stages and overall survival at stage IV (p = 0.013). Elevated MSI2 expression on RNA level was observed in primary tumor versus normal tissue samples in TCGA (p < 0.0001), and positively correlated with decreased OS (p = 0.028). No correlation was observed between MSI2 expression and age, sex, smoking, and treatment type. Conclusions: Elevated MSI2 expression in primary NSCLC tumors is associated with poor prognosis and can be used as a novel potential prognostic biomarker in NSCLC patients. Future studies in an extended patient cohort are strongly warranted.
A multicenter real-world study of tumor-derived DNA from pleural effusion supernatant in genomic profiling of advanced lung cancer.
Authors: Guo Renhua , Chen Likun , Zhou Chengzhi , Ai Xinghao , Zhao Jun , Chen Rongrong , Xia Xuefeng
Published: May 2020

e21584

Background: Pleural effusion (PE) is commonly observed in advanced lung cancer. Researches have suggested molecular profiling of PE represents a minimally invasive approach of detecting tumor driver mutations for clinical decision making. The objective of this study is to investigate the efficacy and precision of detecting gene alterations in PE samples in the real world setting. Methods: 656 metastatic lung cancer patients with pleural effusion were enrolled in this study. Seven hundred and thirty-two samples, including 351 samples of PE supernatant, 224 plasma, 138 tissue, and 25 PE sediments from these patients were collected and subjected to targeted next-generation sequencing (NGS) of 1021 cancer-related genes in a real world setting. The efficacy of pleural effusion in detecting actionable mutations and identifying resistant mechanisms of targeted therapy were analyzed by comparing different samples. Results: Among the 656 NSCLC patients, 413 were in M1a stage and 243 were in M1b/M1c stage, while 272 were newly diagnosed and 384 was previously treated. When comparing different groups of stage and therapeutic history, PE supernatant was preferred as the choice for those patients (46.6% - 48.2% vs 23.3%-34.8% of plasma vs 16.8%-21.2% of tissue and 0.96%-7.3% of PE sediment). While mutant allele frequency (MAFs) of plasma in patients of M1a stage was significantly lower than that of M1b/c stages, MAFs was similar for PE supernatant. EGFR, KRAS, MET, ALK, BRAF, ERBB2, ROS1, and RET actionable mutations were identified in 60, 12, 9, 7, 6, 3, 2, and 1 of the 118 PE supernatant samples at M1a stage taken before treatment. PE-supernatant demonstrated higher sensitivity than plasma of detecting actionable mutations in M1a disease (84.7% of PE-supernatant vs 42.1% of plasma, p < 0.01) but not in M1b/c stages (80.7% of PE-supernatant vs 86.4% of plasma). Seventy-two of the 117 patients who were resistant to 1st or 2nd generation of EGFR-TKI, 22 of the 42 patients resistant to osimertinib, and 9 of the 13 patients resistant to crizotinib had known resistant mutations identified. Remarkably, PE supernatant outperformed plasma in identifying resistant mutations to 1st/2nd generation EGFR-TKI (75.4% vs 29.8%, p < 0.001). Conclusions: This real world large cohort study verified that genomic profiling of PE-supernatant has higher actionable mutation detection sensitivity than plasma. It offers an alternative approach in assessing tumor genomics in advanced lung cancer when tumor tissue is not available.
Neutrophil to lymphocyte ratio and lipi score prognostic value in patients with non-small cell lung cancer in a Mexican population.
Authors: Reyes Eduardo , Martínez-Herrera José Fabián , Andrade Moreno Raul Alejandro , Lara - Torres Cesar , Amador García Geovani , Villalobos Prieto Alberto , Aguayo Alvaro , Serrano Juan Alberto , Gerson Raquel , Olivares Guillermo
Published: May 2020

e21593

Background: Non-Small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for most of all cancer-related morbidity and deaths in the World. Recent Evidence shows that inflammatory response is associated with a poor prognostic in several cancers. Evaluating these markers is of great importance to classify patients of solid tumors including NSCLC. Inflammatory markers like, Glasgow Prognostic Score (GPS), Lung Immune prognostic index (LIPI) and C-Reactive Protein (CRP) have been associated with poor prognosis in patients treated with immune checkpoint inhibitors. Neutrophil to Lymphocyte Ratio (NLR) is a biomarker for the general immune response to various stress stimuli in peripheral blood. It can be easily determined, inexpensive and can correlate with poor outcomes. Methods: A review of medical records was performed including patients from January 2013 to December 2018. The clinical characteristics were described, analyzed and the NLR and the LIPI were calculated. Categorical variables were analyzed with Chi-square test and the correlation was analyzed with the Pearson correlation coefficient. Variables were included in the construction of survival models through Cox multivariate regression using statistical software: STATA SE ver11.0 (StataCorp LLC Texas,USA). Results: A total of 175 patients with complete medical record and pathology samples were included. Around half of patients were female. The mean age was 69 years ± 11 years. The most frequent histology was Adenocarcinoma in 87%, Epidermoid 10% and others 3%. The most frequent mutations were KRAS 25%, EGFR 22% and ALK 1%. PDL-1 > 1% was determined in 20% of patients. Clinical stage IV was found in 58% of the cases followed by Clinical Stage I, II and III with 25%, 9%, 8% respectively. The NLR > 4 is associated with a worse prognosis in Stage I and II HR = 5.4 (95% CI 1.73 - 17.17, p = 0.004). LIPI > 2 had predictive capacity for progression in Stage IV HR = 8.2 (IC 95 % 2.39-23.4, p = < 0.001). Conclusions: NLR > 4 showed prognostic value for recurrence in early clinical stages. LIPI score > 2 resulted in higher risk for progression in metastatic stages. Determination of these indexes has the potential as a readily available prognostic indicator for patients.
Factors influencing disease control in metastatic lung cancer with intracranial metastasis post gamma-knife radiotherapy.
Authors: Tam Laura , Pinkham Mark B. , O'Byrne Kenneth John , Ladwa Rahul
Published: May 2020

e21602

Background: Traditionally, disease control of brain metastases (BM) has dictated the prognosis of those with metastatic lung cancer. Immune check-point inhibitors (ICI) have shown intracranial response but data on the magnitude of such effect in combination with radiation is still evolving. We report the time to progression of intracranial and systemic disease post gamma-knife radiation (GK) and associations with the use of ICI in this cohort. Methods: Patients with metastatic lung cancer with BM treated with GK between 2015 and 2019 were retrospectively analysed in a single institution at the Princess Alexandra Hospital, Queensland. The primary endpoint was time from first GK to death. Results: 104 patients were eligible. Median age was 63 years. BM was seen in 46.7% at diagnosis (versus relapsed in brain). Solitary BM was seen in 37.1% patients. 7.7% had prior whole-brain radiation (WBRT) prior to GK. 45.7% received ICI either at the time of GK or as the next line of treatment immediately post GK. 56.2% received ICI at any time during the study period. Oncogenic driver mutations were seen in 13 cases [EGFR mutant (9.5%), ALK mutation (2.5%)]. 15.2% patients had a high-PDL1 (≥50%) level. Time from GK to death was: 14 (9.7-18.3) months for all patients. Incidence of progressive BM was 46.7%. Time to intracranial PD was 5 months. Systemic PD was seen post GK in 44.8% patients. Survival was improved in those patients with the presence of a driver mutation (p = 0.043) on univariate analysis. Factors which did not impact survival included: the number of BM (solitary vs multiple; p = 0.837), PD-L1 status (PD-L1 < 50% vs ≥50%; p = 0.186), use of ICI (used vs not used; p = 0.307) and previous WBRT (treated vs not treated; p = 0.251). Failure of BM requiring GK on ICI was not associated with a worse outcome (p = 0.707). Conclusions: The presence of driver mutations was associated with prolonged overall survival in select patients undergoing GK for BM. High PDL-1 expressivity and timing of ICI relative to GK do not appear to positively influence outcome in this retrospective study.
Artificial intelligence-assisted CT characterizations and quantitative analysis for differentiating pre-invasive lesions from invasive adenocarcinomas in pulmonary subsolid nodules ≤ 2cm.
Authors: Zhang Bingyu , Yu Fenglei , Peng Muyun
Published: May 2020

e21614

Background: The use of artificial intelligence (AI) in medical imaging has dramatically improved the quality of segmentation including accuracy, efficiency and reproducibility. This study sought to determine whether AI-assisted computed tomography (CT) features and quantitative analysis of pulmonary subsolid nodules (SSNs) under 2cm could be used to differentiate preinvasive lesions from invasive adenocarcinomas. Methods: Clinical data and CT images of 297 preinvasive lesions and early invasive lung adenocarcinomas confirmed by surgery pathology with CT manifestations of SSNs under 2cm were retrospectively analysed. The nodules were divided into two groups: the preinvasive lesions (PILs, N = 115) including 7 cases of atypical adenomatous hyperplasia (AAH), 30 cases of adenocarcinoma in situ (AIS) and 78 cases of minimally invasive adenocarcinoma (MIA), and the invasive adenocarcinomas (IACs, N = 182). All CTs were processed by AI and the volume, mean CT value, consolidation-to-tumor ratio (CTR), mass and maximum diameter of each SSN were obtained. Results: The volume, mean CT value, CTR, maximum diameter and mass of nodules showed significant difference between the two groups (Table). Multivariate analysis was determined by logistic regression. The regression model between the two groups was logit(p) = -1.439-2.927Volume +0.0005(mean CT value)-0.463(CTR > 0.5) +0.238(maximum diameter)+6.298(mass).The receiver operating characteristic curve (ROC) showed that the mass can do the best prediction among all the independent factors with the areas under the curve(AUC) 0.748 at a cut-off value of 0.154, with the sensitivity of 70.9% and specificity of 70.4% .The AUC of the ROC using the regression probabilities of regression model was 0.769. Conclusions: AI-assisted CT characterizations may be promising tools to predict if SSNs under 2 cm have invaded. [Table: see text]
Disease monitoring and TKI resistance mutations of EGFR mutation-positive NSCLC patients via circulating tumor DNA.
Authors: Woestmann Corinna , Ju Christine , Hinzmann Bernd , Yaung Stephanie J. , Thomas Michael , Heussel Claus Peter , Kriegsmann Mark , Meister Michael , Schneider Marc , Herth Felix , Muley Thomas , Wehnl Birgit , Palma John F. , Jiang Yuqiu
Published: May 2020

e21627

Background: 15–40% of NSCLC adenocarcinoma patients harbor EGFR sensitizing mutations. Tyrosine kinase inhibitors (TKI) provide significant clinical benefit in this population, yet all patients will develop resistance. Liquid biopsy has been demonstrated to reliably identify tumor associated somatic EGFR mutations. Quantitative assessment of mutated EGFR driven tumors could potentially be used to monitor disease progression, to assess therapeutic response, and to identify resistance mechanisms. Methods: 106 longitudinal plasma samples from 16 NSCLC patients who were treated with osimertinib as either first line or second line therapy were collected. A series of plasma samples collected during treatment and at the time of disease progression were analyzed with the AVENIO ctDNA Surveillance kit*. Mutations at each time point were identified and reported by the AVENIO software v2.0*. The mutation profile of each patient at different timepoints along with the treatment journey was examined in combination with clinical outcome data. Results: EGFR sensitizing mutations were detected in all plasma samples by sequencing except in 3 cases. Patients responsive to anti-EGFR therapy showed a rapid decrease of EGFR driver mutations to non-detectable levels. Meanwhile, patients who had stable disease or rapid disease progression had stable or slightly decreasing ctDNA levels after receiving the treatment. One patient had a MET amplification, FBXL7 SNV, and EGFR T790M detected at the time of disease progression which were not detected at baseline. One patient had both EGFR L858R and T790M mutations. This patient progressed very quickly on erlotinib. Detection of the T790M mutation decreased upon osimertinib administration, however, the L858R mutation level stayed the same. TP53 mutations were elevated in 3 patients at the time of progression, and could potentially be related to anti-EGFR resistance. Conclusions: This study clearly demonstrated that liquid biopsy could identify resistance mutations beyond EGFR prior to clinical progression. Plasma samples collected prior to or at disease progression could facilitate identification of novel resistant mutations to TKI therapy. Further studies to demonstrate the clinical utility of serial blood EGFR testing in NSCLC management are necessary. *For Research Use Only. Not for use in diagnostic procedures.
Poor performance status and front-line pembrolizumab in advanced non-small-cell lung cancer (NSCLC) patients with PD-L1>50%.
Authors: Addeo Alfredo , Metro Giulio , Signorelli Diego , Economopoulou Panagiota , Roila Fausto , Banna Giuseppe Luigi , De Toma Alessandro , Camerini Andrea , Christopoulou Athina , Lo Russo Giuseppe , Galetta Domenico , Jimenez Munarriz Beatriz , Collazo Ana , Calles Antonio , Baxevanos Panagiotis , Linardou Helena , Kosmidis Paris A. , Mountzios Giannis Socrates , Garassino Marina Chiara , Friedlaender Alex
Published: May 2020

e21651

Background: We retrospectively analysed real-world clinical outcomes of patients with advanced non-small-cell lung cancer (NSCLC) harbouring high PD-L1 expression ( > 50%) and treated with first-line pembrolizumab, following the Keynote 024 regimen. In the recent PePS2 trial and Checkmate 817, we see that some patients with PS2 could benefit from a durable response to checkpoint inhibitors. However, current data does not suggest an improvement in median OS compared to historical data on chemotherapy in this setting. Methods: Data was collected by 16 participating centers. The trial was approved by local ethics committees and patients included signed a general consent form. All patients with NSCLC with PD-L1 expression ≥50%, treated with first-line pembrolizumab were included, from the introduction of first-line pembrolizumab to the present. We collected medical data from patient files, pathology reports and laboratory reports for all patients. Patient characteristics, comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and tumor characteristics were reported. Overall survival (OS) was calculated from the date of the first cycle of pembrolizumab to death and estimated through the Kaplan-Meier method. Results: 302 patients were identified, of which 247 with a PS of 0-1, 52 with a PS of 2. Patients (3) with PS3 were excluded. The median age was 69 with a range from 19 to 87 years. There were 193 males and 106 females, 90% were active or former smokers, 19% had brain lesions at diagnosis. Only 14% received brain radiotherapy. Median OS was 7.2 months among patients with PS2, while not reached for those with PS0-1 (HR 3.80, 95% confidence interval 2.49-5.78). Conclusions: Patients with a PS of 2 had significantly worse survival than those with PS0-1. The retrospective nature of our trial and lack of a control arm treated with chemotherapy do not allow us to postulate as to whether PS is predictive or prognostic. Our data suggests worse survival among NSCLC patients with PS2 treated with front-line pembrolizumab. A prospective randomized trial comparing immunotherapy to chemotherapy or chemo-immunotherapy in this population would be welcome.