G48A, a New KRAS Mutation Found in Lung Adenocarcinoma.

A new somatic mutation in the coding region of Kirsten rat sarcoma viral oncogene homolog gene (KRAS), G48A, has been identified in a patient with non-small cell lung cancer (NSCLC). No other mutations were found by screening several genes known to be mutated in NSCLC. The patient responded to first-line therapy and is still under maintenance treatment 18 months after diagnosis.

Deciphering intra-tumor heterogeneity of lung adenocarcinoma confirms that dominant, branching, and private gene mutations occur within individual tumor nodules.

While pulmonary adenocarcinoma (ADC) is morphologically heterogeneous, little is known about intra-tumor gene mutation heterogeneity (ITH). We therefore subjected 20 ADC nodules, 5 mutated for EGFR and 5 for KRAS, 5 with an ALK translocation, and 5 wild type (WT) for these alterations, to unsupervised next-generation sequencing of tumor regions from diverse architectural patterns. When 2 or more different gene mutations were found in a single tumor, this fulfilled the criteria for ITH.

Is the chemotherapy era in advanced non-small cell lung cancer really over? Maybe not yet.

Lung cancer is one of the most frequently diagnosed tumors in both the male and female population. In Italy it is the leading cause of cancer deaths in men and the third in women. Although the 5-year survival rate has moderately increased in the last years, the diagnosis remains associated with a very poor prognosis.

Afatinib in the treatment of squamous non-small cell lung cancer: a new frontier or an old mistake?

Lung squamous cell carcinoma represents approximately 20% of all non-small cell lung cancer (NSCLC) and is associated with a very poor prognosis. In the randomized phase III LUX-Lung 8 trial afatinib showed a statistical significant efficacy advantage compared to erlotinib as second-line treatment of advanced/metastatic squamous NSCLC. Despite its well-built design and the statistical significant results, in our opinion the study is still far from being clinically relevant for this subset of patients.

Treatment of lung large cell neuroendocrine carcinoma.

Lung large cell neuroendocrine carcinoma (L-LCNEC) is a rare, aggressive, and difficult-to-treat tumor. It is classified as a neuroendocrine subtype of large cell lung carcinoma (LCLC) belonging to the non-small cell lung cancer (NSCLC) group, but it is also included in the neuroendocrine tumor (NET) group. Most of the available data related to its treatment derive from retrospective analyses or small case series.

Diagnosis and management of typical and atypical lung carcinoids.

An estimated 20% to 30% of all neuroendocrine tumours originate in the bronchial tree and lungs. According to the 2015 World Health Organization categorization, these tumours are separated into four subtypes characterized by increasing biological aggressiveness: typical carcinoid, atypical carcinoid, large-cell neuroendocrine carcinoma and small-cell carcinoma. Although typical and atypical lung carcinoids account for less than 1-5% of all pulmonary malignancies, the incidence of these neoplasms has risen significantly in recent decades.

Doing more with less: fluorescence in situ hybridization and gene sequencing assays can be reliably performed on archival stained tumor tissue sections.

Little is known about molecular testing on tumor tissue retrieved from stained sections, for which there may be a clinical need. We retrospectively analyzed 112 sections from 56 tumor patients using either fluorescence in situ hybridization (FISH) with different probes (19 sections from 17 patients) or Sanger or targeted next generation sequencing for detection of BRAF, EGFR, KRAS, C-KIT, and TP53 mutations (93 sections from 39 patients). Tumor tissue sections had been stained by hematoxylin and eosin (H&E) (42 sections) or by immunohistochemistry for cytoplasmic or nuclear/nuclear-cytoplasmic markers (70 sections) with a peroxidase (P-IHC, with 3,3'-diaminobenzidine as chromogen) or alkaline phosphatase label (AP-IHC, with Warp Red™ as chromogen).

Thymoma and thymic carcinomas.

Thymomas (Ts) and thymic carcinomas (TCs) are rare tumours of the mediastinum with an incidence rate of 1.7/million per year in Europe. Histological classification is based on rate of non-malignant-appearing thymic epithelial cells and proportions of lymphocytes (A, AB, B1, B2, B3, and C), while staging system concerns localisation of the involved areas.

Moving towards a customized approach for drug development: lessons from clinical trials with immune checkpoint inhibitors in lung cancer.

Lung cancer has recently been discovered to be an immunological targetable disease, on the basis of the exciting results of the randomized trials with immune checkpoint inhibitors. Nevertheless, the survival benefit appears to not be entirely captured by the usual outcome measures, thus requiring a deep reflection about the appropriateness of the traditional statistical methodologies in this context. The intrinsic biological differences existing both in terms of mechanism of action and kinetic between immunotherapy and chemotherapy or targeted therapy, impact on patients' outcome, requiring a global revolution in the way to design clinical studies with the ideal aim to evolve towards trials carefully 'customized' on the basis of the investigational drug, the specific disease and the biological background.

Role of KRAS-LCS6 polymorphism in advanced NSCLC patients treated with erlotinib or docetaxel in second line treatment (TAILOR).

MicroRNAs were described to target mRNA and regulate the transcription of genes involved in processes de-regulated in tumorigenesis, such as proliferation, differentiation and survival. In particular, the miRNA let-7 has been suggested to regulate the expression of the KRAS gene, a common mutated gene in non-small cell lung cancer (NSCLC), through a let-7 complementary site (LCS) in 3'UTR of KRAS mRNA. We have reported the analysis performed on the role of the polymorphism located in the KRAS-LCS (rs61764370) which is involved in the disruption of the let-7 complementary site in NSCLC patients enrolled within the TAILOR trial, a randomised trial comparing erlotinib versus docetaxel in second line treatment.

Systemic approach to malignant pleural mesothelioma: what news of chemotherapy, targeted agents and immunotherapy?

Malignant pleural mesothelioma is a rare cancer with a cause-effect relationship to asbestos exposure. The prognosis is poor and chemotherapy seems the best treatment option. In the last two decades a deeper understanding of mesothelioma carcinogenesis and invasiveness mechanisms has prompted research efforts to test new agents in patients with malignant pleural mesothelioma, but the results have been modest.

New findings on thymic epithelial tumors: Something is changing.

Thymic epithelial tumors (TETs) are uncommon neoplasms with a wide range of anatomical, clinical, histological and molecular malignant entities. To date the management of TETs within clinical practice is based on a multimodal therapeutic strategy including surgery, chemotherapy and radiotherapy with a multidisciplinary approach and prognostic evaluation is mainly based on Masaoka staging and World Health Organization classification. Therefore novel strategies are needed, especially for refractory and/or recurrent TETs and for thymic carcinomas that present a poor prognosis.

KRAS mutations affect prognosis of non-small-cell lung cancer patients treated with first-line platinum containing chemotherapy.

Unlabelled: KRAS mutations seem to indicate a poor outcome in Non-Small-Cell Lung Cancer (NSCLC) but such evidence is still debated. The aim of this planned ancillary study within the TAILOR trial was to assess the prognostic value of KRAS mutations in advanced NSCLC patients treated with platinum-based first-line chemotherapy. Patients (N = 540), enrolled in the study in 52 Italian hospitals, were centrally genotyped twice in two independent laboratories for EGFR and KRAS mutational status.

Base excision repair-mediated resistance to cisplatin in KRAS(G12C) mutant NSCLC cells.

KRAS mutations in NSCLC are supposed to indicate a poor prognosis and poor response to anticancer treatments but this feature lacks a mechanistic basis so far. In tumors, KRAS was found to be mutated mostly at codons 12 and 13 and a pool of mutations differing in the base alteration and the amino acid substitution have been described. The different KRAS mutations may differently impact on cancerogenesis and drug sensitivity.

Dissecting Pulmonary Large-Cell Carcinoma by Targeted Next Generation Sequencing of Several Cancer Genes Pushes Genotypic-Phenotypic Correlations to Emerge.

Introduction: Little is known about genotypic and phenotypic correlations in undifferentiated large-cell carcinoma (LCC) of the lung.

Methods: Thirty LCC were dissected by unsupervised targeted next generation sequencing analysis for 50 cancer-associated oncogenes and tumor suppressor genes. Cell differentiation lineages were unveiled by using thyroid transcription factor-1 (TTF1) for adenocarcinoma (ADC) and p40 for squamous cell carcinoma (SQC), dichotomizing immunohistochemistry (IHC) results for TTF1 as negative or positive (whatever its extent) and for p40 as negative, positive, or focal (if <10% of reactive tumor cells).

Value of KRAS as prognostic or predictive marker in NSCLC: results from the TAILOR trial.

Background: The prognostic and predictive role of KRAS mutations in advanced nonsmall-cell lung cancer (NSCLC) is still unclear. TAILOR prospectively assessed the prognostic and predictive value of KRAS mutations in NSCLC patients treated with erlotinib or docetaxel in second line.

Patients And Methods: NSCLC patients from 52 Italian hospitals were genotyped for KRAS and EGFR mutational status in two independent laboratories.

Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.

Background: Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population.

Methods: We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks.

Is there evidence for different effects among EGFR-TKIs? Systematic review and meta-analysis of EGFR tyrosine kinase inhibitors (TKIs) versus chemotherapy as first-line treatment for patients harboring EGFR mutations.

Three EGFR tyrosine kinase inhibitors have been compared to standard chemotherapy as up-front treatment in patients with advanced EGFR-positive NSCLC. We performed a systematic review and meta-analysis using indirect comparisons to estimate the risk/benefit associated with each drug. EGFR-TKIs fared better than chemotherapy in terms of PFS.

Available evidence and new biological perspectives on medical treatment of advanced thymic epithelial tumors.

Thymic epithelial tumors (TETs) are rare primary mediastinal tumors arising from thymic epithelium. Their rarity and complexity hinder investigations of their causes and therapy development. Here, we summarize the existing knowledge regarding medical treatment of these tumors, and thoroughly review the known genetic aberrations associated with TETs and the present status of potential biological treatments.