Identification of a 17-protein signature in the serum of lung cancer patients.

Early detection of lung cancer may potentially help to improve the outcome of this fatal disease. Currently, no satisfactory laboratory tests are available to screen for this type of cancer. The aim of this study was to improve diagnostic procedures for lung cancer through the discovery of serum biomarkers using SELDI-TOF MS (surface-enhanced laser desorption/ionization time-of-flight mass spectrometry). Mass spectrometric profiling was applied to the serum of a total of 139 lung cancer patients and 158 healthy individuals for developing a prognostic signature. For validation, two separate groups were employed, comprising of 126 and 50 individuals, respectively. Informative regions of mass spectra were identified by forming protein mass clusters and identifying predictive clusters in a logistic regression model. A total of 17 differential predictive protein mass clusters were identified in patients with metastatic lung cancer disease compared to healthy individuals. These clusters provide for a robust risk prediction model. The sensitivity and specificity of this model was estimated to be 87.3 and 81.9%, respectively, for the first validation set, and 96.0 and 66.7%, respectively, for a second validation set of patients with early disease (stages I and II). A differential 11.5/11.7 kDa double-peak could be identified as serum amyloid alpha (SAA) by peptide mapping. Our data suggest that the SELDI-TOF MS technology in combination with a careful statistical analysis appears to be a useful experimental platform which delivers a rapid insight into the proteome of body fluids and may guide to identify novel biomarkers for lung cancer disease.

Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer: an analysis of patients from german centers in the TRUST study.

INTRODUCTION: Relationships between clinical outcomes and epidermal growth factor receptor (EGFR)-related tumor markers were investigated in patients with advanced non-small cell lung cancer. METHODS: Patients with stage IIIB/IV non-small cell lung cancer (0-2 prior regimens) received erlotinib (150 mg PO per day). Response and survival were evaluated, and tumor samples were assessed by immunohistochemistry (EGFR, phosphorylated mitogen-activated protein kinase, and phosphorylated AKT protein expression), fluorescence in situ hybridization (FISH; EGFR gene copy number), and DNA sequencing (EGFR, KRAS gene mutations). RESULTS: Among 311 patients, 8% had a complete/partial response; the disease control rate was 66%. Median Overall survival (OS) was 6.1 months; 1-year survival rate was 27.2%. Two of 4 patients with EGFR mutations had tumor responses, versus 2/68 with wild-type EGFR (p = 0.014). Progression-free survival (PFS) (HR = 0.31) and OS (HR = 0.33) were significantly prolonged in patients with EGFR mutations. Response rate was significantly higher in patients with EGFR FISH-positive (17%) than FISH-negative tumors (6%), and both PFS (HR = 0.58) and OS (HR = 0.63) significantly favored patients with EGFR FISH-positive tumors; median OS was 8.6 months in the EGFR FISH-positive group. None of 17 patients with a KRAS mutation had a tumor response, but the impact of KRAS mutation status on survival outcomes was of borderline statistical significance. Neither phosphorylated mitogen-activated protein kinase nor phosphorylated AKT immunohistochemistry status had a significant effect on PFS and OS with erlotinib. CONCLUSIONS: The presence of EGFR mutations and EGFR FISH-positive tumors may predispose patients to achieving better outcomes on erlotinib, but may have a beneficial impact on prognosis (irrespective of treatment). Prospective, placebo-controlled studies are needed to determine the predictive value of the putative biomarkers.

DNA methylation disturbances as novel therapeutic target in lung cancer: preclinical and clinical results.

The prognosis of lung cancer is very much limited by the difficulties of diagnosing early stage disease amenable to surgery. Thus, novel diagnostic and therapeutic approaches are urgently needed for this common type of cancer. Recently, epigenetic alterations of tumor cells have been defined for a multitude of tissues and genes. Thus, promoter hypermethylation of tumor suppressor genes, and other targets of neoplasia-associated methylation disturbances, have become the most frequent recurrent alteration in solid tumors and hematologic neoplasia. In lung cancer, several sets of genes including the tumor suppressor gene p16, the DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT), E-cadherin and retinoic acid receptor beta have been shown to be frequently methylated and inactivated. Distinct methylation patterns can provide molecular distinctions between different histologic subtypes of lung cancer. Gene hypermethylation in lung cancer is an early event associated with exposure to tobacco-specific carcinogens. Highly sensitive detection of hypermethylated DNA in sputum and peripheral blood offers a powerful tool for detecting lung cancer at an early stage. Epigenetic alterations in cancer, as opposed to genetic lesions, are potentially reversible. Thus, hypermethylation has been studied as a therapeutic target for agents which revert this epigenotype. The most advanced drugs to inhibit methylation are two azanucleosides, decitabine and its ribonucleoside analogue 5-azacytidine. In vitro, demethylating agents given at low doses reactivate tumor suppressor genes, and in mouse models, the development of lung cancer can be retarded. This effect is more powerful when histone acetylation, as a second epigenetic silencing mechanism, is also inhibited pharmacologically (HDAC inhibitors). Clinical trials of both groups of agents have been performed, and novel demethylating agents which are not incorporated into DNA offer further perspectives for epigenetic therapy of lung cancer and other malignancies.

Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia.

We treated 45 adult patients with T-lymphoblastic lymphoma (T-LBL) (age range 15-61 years) with 2 protocols designed for adult acute lymphoblastic leukemia (ALL). An encouraging cure rate of 90% was recently reported for T-LBL in children treated with a similar approach. In our study, an 8-drug standard induction was administered over 8 weeks including prophylactic cranial (24 Gy) and mediastinal irradiation (24 Gy) followed by consolidation and reinduction therapy. At diagnosis, 91% of the 45 patients showed a mediastinal tumor and 40% had pleural/pericardial effusions; 73% of the patients had stage III/IV disease. Overall, 42 patients (93%) achieved a complete remission (CR), 2 patients (4%) achieved a partial remission, and 1 patient (2%) died during induction. In patients with stage I-III disease (n = 18) the CR rate was 100% compared with 89% in stage IV (n = 27). There were 15 patients who relapsed (36%) within 12 months. The majority of relapses (47%) occurred in the mediastinum (n = 7) despite mediastinal irradiation with 24 Gy in 6 out of 7 patients. The estimates for overall survival, continuous CR, and disease-free survival at 7 years are 51%, 65%, and 62%, respectively. Stage, age, lactate dehydrogenase, and all other parameters had no influence on achievement of CR or outcome. This study demonstrates in a large cohort of patients with adult T-LBL that a high CR rate and a favorable outcome can be achieved with an ALL-type regimen. Mediastinal recurrence was the major obstacle and further improvement by intensification of chemotherapy, increased dose of mediastinal irradiation (36 Gy), and extended indications for stem cell transplantation seem to be required.