Next-generation sequencing reveals novel resistance mechanisms and molecular heterogeneity in EGFR-mutant non-small cell lung cancer with acquired resistance to EGFR-TKIs.

Objectives: Despite initial responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutant non-small cell lung cancer, patients invariably develop acquired resistance. In this study, we performed next-generation sequencing in pre- and post-EGFR-TKI tumor samples to identify novel resistance mechanisms to EGFR-TKIs.

Material And Methods: We collected tumor tissues before EGFR-TKI treatment and after progression from 19 NSCLC patients to analyze genomic alterations in 409 cancer related genes.

A Clinical Trial of Combination Neoadjuvant Chemotherapy and Transoral Robotic Surgery in Patients with T3 and T4 Laryngo-Hypopharyngeal Cancer.

Background: We conducted a prospective clinical trial of combination neoadjuvant chemotherapy, transoral robotic surgery (TORS), and customized adjuvant therapy in patients with locally advanced laryngo-hypopharyngeal cancer.

Methods: Between September 2008 and August 2016, 35 patients were enrolled in this clinical trial.

Results: Twenty patients had hypopharyngeal cancer and 15 had laryngeal cancer.

Activity and safety of AZD3759 in EGFR-mutant non-small-cell lung cancer with CNS metastases (BLOOM): a phase 1, open-label, dose-escalation and dose-expansion study.

Background: CNS metastases-including brain and leptomeningeal metastases-from epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) are associated with poor prognosis. AZD3759 is a novel EGFR tyrosine kinase inhibitor with high capability to penetrate the blood-brain barrier. We aimed to assess the safety, tolerability, pharmacokinetics, and efficacy of AZD3759 in patients with EGFR-mutant NSCLC with brain and leptomeningeal metastases.

Efficacy and safety of vinorelbine plus cisplatin chemotherapy for patients with recurrent and/or metastatic salivary gland cancer of the head and neck.

Background: The purpose of this study was to investigate the efficacy and safety of vinorelbine plus cisplatin chemotherapy in patients with recurrent and/or metastatic salivary gland cancer of the head and neck.

Methods: In this single-arm phase II study, patients with recurrent and/or metastatic salivary gland cancer were treated with i.v.

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.

Architectural patterns of p16 immunohistochemical expression associated with cancer immunity and prognosis of head and neck squamous cell carcinoma.

We evaluated the expression patterns of p16, which is used as a surrogate marker of HPV infection in head and neck squamous cell carcinoma (HNSCC), in regard to their biological and prognostic implications. p16 expression patterns and infiltrated immune cells were analyzed through immunohistochemistry of p16, CD3, CD8, PD-1, FOXP3, and CD163 on surgically resected HNSCCs (n = 393). Patterns of p16 immunoexpression were defined as STRONG (strong, diffuse expression in cytoplasm, and nucleus in >70% of tumor cells), MARGINAL (expression restricted to tumor margins), MOSAIC (ragged, discontinued expression), NUCLEAR (expression in nuclei only), and ABSENT (no expression).

Correction: A randomized, phase II study of gefitinib alone versus nimotuzumab plus gefitinib after platinum-based chemotherapy in advanced non-small cell lung cancer (KCSG LU12-01).

[This corrects the article DOI: 10.18632/oncotarget.13056.

Validation of ALK/ROS1 Dual Break Apart FISH Probe probe in non-small-cell lung cancer.

Background: ALK and ROS1 gene rearrangements are distinct molecular subsets of non-small-cell lung cancer (NSCLC), and they are strong predictive biomarkers of response to ALK/ROS1 inhibitors, such as crizotinib. Thus, it is clinically important to develop an effective screening strategy to detect patients who will benefit from such treatment. In this study, we aimed to validate analytical performance of Vysis ALK/ROS1 Dual Break Apart Probe Kit (RUO) in NSCLC.

ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non-Small Cell Lung Cancer (NSCLC).

Introduction: Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure.

Methods: ASCEND-8 is a multicenter, randomized, open-label, phase 1 study.

Optimal dose and volume for postoperative radiotherapy in brain oligometastases from lung cancer: a retrospective study.

Purpose: To evaluate intracranial control after surgical resection according to the adjuvant treatment received in order to assess the optimal radiotherapy (RT) dose and volume.

Materials And Methods: Between 2003 and 2015, a total of 53 patients with brain oligometastases from non-small cell lung cancer (NSCLC) underwent metastasectomy. The patients were divided into three groups according to the adjuvant treatment received: whole brain radiotherapy (WBRT) ± boost (WBRT ± boost group, n = 26), local RT/Gamma Knife surgery (local RT group, n = 14), and the observation group (n = 13).

Treatment options for EGFR mutant NSCLC with CNS involvement-Can patients BLOOM with the use of next generation EGFR TKIs?

With the use of EGFR TKIs, patient survival is now prolonged and as a consequence, a higher chance of development of CNS metastases has been observed during the course of the disease. CNS metastases remains a therapeutically challenging subset of patient to treat owing to the blood-brain barrier (BBB). Prior to routine EGFR mutation testing, surgical resection, stereotactic radiosurgery and/or whole brain radiation therapy (WBRT) were the main treatment options whereas treatment options for patients with leptomeningeal metastases (LM) included intra-thecal chemotherapy, WBRT, and ventriculo-peritoneal shunting.

Open-Label, Multicenter, Phase II Study of Ceritinib in Patients With Non-Small-Cell Lung Cancer Harboring ROS1 Rearrangement.

Purpose ROS1 rearrangement is a distinct molecular subset of non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of ceritinib in patients with ROS1-rearranged NSCLC. Patients and Methods We enrolled 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement by fluorescent in situ hybridization.

Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry.

Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement.

Activation of Transforming Growth Factor Beta 1 Signaling in Gastric Cancer-associated Fibroblasts Increases Their Motility, via Expression of Rhomboid 5 Homolog 2, and Ability to Induce Invasiveness of Gastric Cancer Cells.

Background & Aims: Fibroblasts that interact with cancer cells are called cancer-associated fibroblasts (CAFs), which promote progression of different tumor types. We investigated the characteristics and functions of CAFs in diffuse-type gastric cancers (DGCs) by analyzing features of their genome and gene expression patterns.

Methods: We isolated CAFs and adjacent non-cancer fibroblasts (NFs) from 110 gastric cancer (GC) tissues from patients who underwent gastrectomy in Japan from 2008 through 2016.

Randomized phase II study comparing weekly docetaxel-cisplatin vs. gemcitabine-cisplatin in elderly or poor performance status patients with advanced non-small cell lung cancer.

Background: Docetaxel/cisplatin (DP) and gemcitabine/cisplatin (GP) are standard treatment regimens for advanced non-small cell lung cancer (NSCLC). In spite of potent efficacy, the conventional 1-day DP is regarded as having more toxicity as compared with GP. There is increasing interest in a biweekly split administration of DP to reduce its toxicity.

Impact of a planned dose interruption of dacomitinib in the treatment of advanced non-small-cell lung cancer (ARCHER 1042).

Objectives: Dacomitinib is a pan-HER inhibitor for advanced non-small-cell lung cancer (NSCLC). We explored the impact of a planned 4-day dacomitinib dose interruption on plasma exposure of dacomitinib and adverse events (AEs) of interest in Cohort III of the ARCHER 1042 study.

Materials And Methods: Patients, treatment-naïve for advanced NSCLC with EGFR activating mutations, received oral dacomitinib 45mg QD (once daily).

Significance of immune checkpoint proteins in EGFR-mutant non-small cell lung cancer.

Objectives: To characterize the expression of PD-L1, PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and T-cell immunoglobulin and mucin-domain containing-3 (TIM3) in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC).

Materials And Methods: Samples from 90 patients with newly diagnosed advanced stage NSCLC harboring EGFR mutations and treated with first line EGFR tyrosine kinase inhibitors (TKI) within 3 months of diagnosis were stained for CTLA-4, PD-L1, PD-1, TIM-3 and CD3 expression by immunohistochemistry.

Results: PD-L1 was present in at least 1% of immune and tumor cells in 44% and 59% of samples, respectively.

Predictive factors of early distant brain failure after gamma knife radiosurgery alone in patients with brain metastases of non-small-cell lung cancer.

The objective of this study was to elucidate the predictive factors for early distant brain failure in patients with brain metastases of non-small-cell lung cancer (NSCLC) who were treated with gamma knife radiosurgery (GKRS) without previous whole-brain radiotherapy (WBRT) or surgery. We retrospectively reviewed clinical and imaging data of 459 patients with brain metastases of NSCLC who underwent GKRS from June 2008 to December 2013. The primary end-point was early distant brain failure, defined as the detection of newly developed metastatic lesions on magnetic resonance imaging (MRI) 3 months after GKRS.

Alteration status and prognostic value of MET in head and neck squamous cell carcinoma.

The MET pathway plays a key role in various cancers, and its inhibition represents a potential treatment target. However, appropriate biomarkers are needed to facilitate the selection of patients who would benefit from MET inhibiting therapy. We herein conducted a robust confirmatory evaluation of the copy number alteration status and prognostic significance of c-Met expression in a large series of patients (n = 396) who underwent standard surgical resection and adjuvant chemoradiotherapy for head and neck squamous cell carcinoma (HNSCC).

Clinical course of stage IV invasive mucinous adenocarcinoma of the lung.

Introduction: An invasive mucinous adenocarcinoma (IMA) is a distinct lung adenocarcinoma variant. The characteristics of stage IV IMAs are relatively unclear since most previous studies described resected cases from stage I to III. The present study aimed to investigate the clinical course of stage IV IMAs and compare the findings to those of stage IV invasive non-mucinous adenocarcinomas (INMAs).

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.

Establishment of a Conditional Transgenic Mouse Model Recapitulating EML4-ALK-Positive Human Non-Small Cell Lung Cancer.

Background: Anaplastic lymphoma receptor tyrosine kinase gene (ALK) fusion is a distinct molecular subclassification of NSCLC that is targeted by anaplastic lymphoma kinase (ALK) inhibitors. We established a transgenic mouse model that expresses tumors highly resembling human NSCLC harboring echinoderm microtubule associated protein like 4 gene (EML)-ALK fusion. We aimed to test an EML4-ALK transgenic mouse model as a platform for assessing the efficacy of ALK inhibitors and examining mechanisms of acquired resistance to ALK inhibitors.

A randomized, phase II study of gefitinib alone versus nimotuzumab plus gefitinib after platinum-based chemotherapy in advanced non-small cell lung cancer (KCSG LU12-01).

We aimed to evaluate the efficacy of dual inhibition of epidermal growth factor receptor (EGFR) with nimotuzumab (EGFR monoclonal antibody) plus gefitinib (EGFR-tyrosine kinase inhibitor) in advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy. An open label, randomized, phase II trial was conducted at 6 centers; 160 patients were randomized (1:1) to either gefitinib alone or nimotuzumab (200 mg, i.v.

Optimal Adjuvant Treatment for Curatively Resected Thoracic Esophageal Squamous Cell Carcinoma: A Radiotherapy Perspective.

Purpose: The purpose of this study was to evaluate the benefits of adjuvant treatment for curatively resected thoracic esophageal squamous cell carcinoma (ESCC) and determine the optimal adjuvant treatments.

Materials And Methods: One hundred ninety-five patients who underwent a curative resection for thoracic ESCC between 1994 and 2014 were reviewed retrospectively. Postoperatively, the patients received no adjuvant treatment (no-adjuvant group, n=68), adjuvant chemotherapy (AC group, n=62), radiotherapy (RT group, n=41), or chemoradiotherapy (CRT group, n=24).

Efficacy and safety of dovitinib in pretreated patients with advanced squamous non-small cell lung cancer with FGFR1 amplification: A single-arm, phase 2 study.

Background: Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential driving oncogene in squamous cell cancer (SCC) of the lung. The current phase 2 study evaluated the efficacy and tolerability of dovitinib, an FGFR inhibitor, in patients with advanced SCC of the lung.

Methods: Patients with pretreated advanced SCC of the lung whose tumors demonstrated FGFR1 amplification of > 5 copies by fluorescence in situ hybridization were enrolled.