Continuous centrifugal microfluidics (CCM) isolates heterogeneous circulating tumor cells via full automation.

Understanding cancer heterogeneity is essential to finding diverse genetic mutations in metastatic cancers. Thus, it is critical to isolate all types of CTCs to identify accurate cancer information from patients. Moreover, full automation robustly capturing the full spectrum of CTCs is an urgent need for CTC diagnosis to be routine clinical practice.

Dynamic changes in circulating PD-1CD8 T lymphocytes for predicting treatment response to PD-1 blockade in patients with non-small-cell lung cancer.

Background: The predictive value of immune monitoring with circulating CD8 T lymphocytes for treatment response to programmed cell death protein 1 (PD-1) inhibitors has not been explored in non-small-cell lung cancer (NSCLC), prompting us to investigate whether dynamic changes in PD-1CD8 T lymphocytes have predictive value for durable clinical benefit (DCB) and survival after PD-1 blockade.

Methods: Patients with recurrent and/or metastatic NSCLC treated with PD-1 inhibitors were enrolled (discovery cohort; n = 94). Peripheral blood was obtained immediately before and after one cycle of treatment with PD-1 blockade.

Mouse-human co-clinical trials demonstrate superior anti-tumour effects of buparlisib (BKM120) and cetuximab combination in squamous cell carcinoma of head and neck.

Background: Recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN) is a common cancer with high recurrence and mortality. Current treatments have low response rates (RRs).

Methods: Fifty-three patients with R/M SCCHN received continuous oral buparlisib.

Genome-wide identification of differentially methylated promoters and enhancers associated with response to anti-PD-1 therapy in non-small cell lung cancer.

Although approved programmed cell death protein (PD)-1 inhibitors show durable responses, clinical benefits to these agents are only seen in one-third of patients in most cancer types. Therefore, strategies for improving the response to PD-1 inhibitor for treating various cancers including non-small cell lung cancer (NSCLC) are urgently needed. Compared with genome and transcriptome, tumor DNA methylome in anti-PD-1 response was relatively unexplored.

Phase 2 study of afatinib among patients with recurrent and/or metastatic esophageal squamous cell carcinoma.

Background: The objective of the current study was to investigate the clinical activity of, safety of, and predictive biomarkers for afatinib, an irreversible pan-ErbB kinase inhibitor, in patients with recurrent and/or metastatic esophageal squamous cell carcinoma (R/M-ESCC).

Methods: Patients with R/M-ESCC that was refractory to platinum-based chemotherapy were enrolled in the current multicenter, single-arm, phase 2 study and received afatinib at a dose of 40 mg/day. The primary endpoint was the objective response rate.

Peripheral natural killer cells and myeloid-derived suppressor cells correlate with anti-PD-1 responses in non-small cell lung cancer.

Inhibition of immune checkpoint proteins like programmed death 1 (PD-1) is a promising therapeutic approach for several cancers, including non-small cell lung cancer (NSCLC). Although PD-1 ligand (PD-L1) expression is used to predict anti-PD-1 therapy responses in NSCLC, its accuracy is relatively less. Therefore, we sought to identify a more accurate predictive blood biomarker for evaluating anti-PD-1 response.

Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR-MET Bispecific Antibody, in Diverse Models of Exon 20 Insertion-Driven NSCLC.

exon 20 insertion driver mutations (Exon20ins) in non-small cell lung cancer (NSCLC) are insensitive to EGFR tyrosine kinase inhibitors (TKI). Amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR-MET, has shown preclinical activity in TKI-sensitive -mutated NSCLC models and in an ongoing first-in-human study in patients with advanced NSCLC. However, the activity of amivantamab in Exon20ins-driven tumors has not yet been described.

Establishment and characterization of patient-derived xenografts as paraclinical models for head and neck cancer.

Background: We investigated whether head and neck squamous cell carcinoma (HNSCC) patient-derived xenografts (PDXs) reaffirm patient responses to anti-cancer therapeutics.

Methods: Tumors from HNSCC patients were transplanted into immunodeficient mice and propagated via subsequent implantation. We evaluated established PDXs by histology, genomic profiling, and in vivo anti-cancer efficacy testing to confirm them as the authentic in vivo platform.

The Interplay between Slow-Cycling, Chemoresistant Cancer Cells and Fibroblasts Creates a Proinflammatory Niche for Tumor Progression.

Quiescent cancer cells are believed to cause cancer progression after chemotherapy through unknown mechanisms. We show here that human non-small cell lung cancer (NSCLC) cell line-derived, quiescent-like, slow-cycling cancer cells (SCC) and residual patient-derived xenograft (PDX) tumors after chemotherapy experience activating transcription factor 6 (ATF6)-mediated upregulation of various cytokines, which acts in a paracrine manner to recruit fibroblasts. Cancer-associated fibroblasts (CAF) underwent transcriptional upregulation of COX2 and type I collagen (Col-I), which subsequently triggered a slow-to-active cycling switch in SCC through prostaglandin E (PGE)- and integrin/Src-mediated signaling pathways, leading to cancer progression.

Dual-targeting of EGFR and Neuropilin-1 attenuates resistance to EGFR-targeted antibody therapy in KRAS-mutant non-small cell lung cancer.

The therapeutic targeting of oncogenic KRAS mutant-harboring (KRAS) non-small cell lung cancer (NSCLC) is an urgent unmet need in cancer therapy. Although NSCLC is often driven by epidermal growth factor receptor (EGFR) overexpression and/or mutations, no EGFR-targeted therapy is clinically available for KRAS NSCLC. In this study, we show that integrin β3 expression is associated with the intrinsic resistance of KRAS NSCLCs to the anti-EGFR antibody cetuximab.

Dynamic changes in PD-L1 expression and CD8 T cell infiltration in non-small cell lung cancer following chemoradiation therapy.

Objectives: The treatment for stage III non-small cell lung cancer (NSCLC) is quite variable because stage III NSCLC is a heterogenous disease. Programmed death ligand 1 (PD-L1) and CD8 tumor infiltrating lymphocytes (TILs) are thought to be related to treatment outcome in many tumors. To improve treatment outcome in stage III NSCLC, it is necessary to obtain data on PD-L1 expression and CD8 TIL counts following CCRT and their relationship to treatment outcome.

Indoor radon exposure increases tumor mutation burden in never-smoker patients with lung adenocarcinoma.

Objectives: Radon, a natural radiation, is the leading environmental cause of lung cancer in never-smokers. However, the radon exposure impact on the mutational landscape and tumor mutation burden (TMB) of lung cancer in never-smokers has not been explored. The aim of this study was to investigate the mutational landscape of lung adenocarcinoma in never-smokers who were exposed to various degrees of residential radon.

Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.

Background: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade.

YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non-Small Cell Lung Cancer.

Purpose: Given that osimertinib is the only approved third-generation EGFR-TKI against activating and resistant T790M mutated non-small cell lung cancer (NSCLC), additional mutant-selective inhibitors with a higher efficacy, especially for brain metastases, with favorable toxicity profile are still needed. In this study, we investigated the antitumor efficacy of YH25448, an oral, mutant-selective, irreversible third-generation EGFR-TKI in preclinical models.

Experimental Design: Antitumor activity of YH25448 was investigated using mutant -expressing Ba/F3 cells and various lung cancer cell lines.

Establishment of a platform of non-small-cell lung cancer patient-derived xenografts with clinical and genomic annotation.

Background: Preclinical models that can better predict therapeutic activity in clinical trials are needed in this era of personalized cancer treatment. Herein, we established genomically and clinically annotated patient-derived xenografts (PDXs) from non-small-cell lung cancer (NSCLC) patients and investigated whether these PDXs would faithfully recapitulate patient responses to targeted therapy.

Methods: Patient-derived tumors were implanted in immunodeficient mice and subsequently expanded via re-implantation.

Concordance of programmed death-ligand 1 expression between primary and metastatic non-small cell lung cancer by immunohistochemistry and RNA hybridization.

We investigated the concordance of programmed death-ligand 1 (PD-L1) expression between primary cancer at initial diagnosis and metastasis at recurrence in resected non-small cell lung cancer (NSCLC). PD-L1 expression was evaluated using the SP142 assay in 37 NSCLC patients with paired primary lung cancer and surgically resected metastases at recurrence. PD-L1 positivity was defined as immunohistochemistry (IHC) and also evaluated by RNA hybridization (RISH).

Detection of activating and acquired resistant mutation in plasma from EGFR-mutated NSCLC patients by peptide nucleic acid (PNA) clamping-assisted fluorescence melting curve analysis.

This study was designed to prospectively examine whether peptide nucleic acid clamping-assisted fluorescence melting curve analysis (PANAMutyper™) is feasible for the detection of activating and acquired resistant () mutation in plasma. Patients with non-small cell lung cancer harboring activating EGFR mutations who were scheduled to undergo EGFR-tyrosine kinase inhibitors (EGFR-TKIs) were enrolled between September 2011 and March 2015. A total of 102 patients with EGFR-mutated lung cancer were enrolled, 53 had available plasma samples at disease progression, and 28 underwent serial plasma sampling during EGFR-TKI treatment.

Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.

Background: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC).

Methods: The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling.

PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients.

To investigate the expression of programmed death-ligand 1 (PD-L1) and immune checkpoints and their prognostic value for resected head and neck squamous cell cancer (HNSCC). PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC), abundance of tumor-infiltrating lymphocytes (TILs), and expression of the immune checkpoints were investigated in 402 HNSCC patients. PD-L1 expression on TC and IC was categorized into four groups according to the percentage of PD-L1-positive cells.

Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy.

Aberrant fibroblast growth factor receptor (FGFR) activation/expression is a common feature in lung cancer (LC). In this study, we evaluated the antitumor activity of and the mechanisms underlying acquired resistance to two potent selective FGFR inhibitors, AZD4547 and BAY116387, in LC cell lines. The antitumor activity of AZD4547 and BAY1163877 was screened in 24 LC cell lines, including 5 with FGFR1 amplification.

EGFR-Mediated Reactivation of MAPK Signaling Induces Acquired Resistance to GSK2118436 in BRAF V600E-Mutant NSCLC Cell Lines.

Although treatment of BRAF V600E-mutant non-small cell lung cancer (NSCLC(V600E)) with GSK2118436 has shown an encouraging efficacy, most patients develop resistance. To investigate the mechanisms of acquired resistance to GSK2118436 in NSCLC(V600E), we established GSK2118436-resistant (GSR) cells by exposing MV522 NSCLC(V600E) to increasing GSK2118436 concentrations. GSR cells displayed activated EGFR-RAS-CRAF signaling with upregulated EGFR ligands and sustained activation of ERK1/2, but not MEK1/2, in the presence of GSK2118436.

Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck.

Dacomitinib, an irreversible pan-HER inhibitor, had shown modest clinical activity in squamous cell carcinoma of head and neck (SCCHN) patients. Therefore, validated predictive biomarkers are required to identify patients most likely to benefit from this therapeutic option. To characterize the genetic landscape of cisplatin-treated SCCHN genomes and identify potential predictive biomarkers for dacomitinib sensitivity, we performed whole exome sequencing on 18 cisplatin-resistant metastatic SCCHN tumors and their matched germline DNA.

Lack of ROS1 Gene Rearrangement in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor, and the prognosis remains poor. Rearrangement of ROS1 gene, which was shown to have an oncogenic potential, was previously discovered in GBM cell lines. In this pilot study, we aimed to identify the incidence of ROS1 rearrangement in GBM patient tissues to explore novel biomarkers for therapeutic strategy.

Antitumor Activity and Acquired Resistance Mechanism of Dovitinib (TKI258) in RET-Rearranged Lung Adenocarcinoma.

RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore antitumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC.