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  • 1
    Abstract: PURPOSE: Lung cancer accounts for one in five cancer deaths. Broad screening strategies for high-risk populations are unavailable, and the validation of biomarkers for early cancer detection remains a prime interest. Therefore, we investigated the value of circulating U2 small nuclear RNA fragments (RNU2-1f) as a biomarker for diagnosis, prognosis estimation and treatment monitoring in a large lung cancer cohort. METHODS: We determined RNU2-1f abundance in sera of patients with treatment-naive lung cancer (n = 211, 25.6 % early stage), chronic lung disease (n = 56) and healthy controls (n = 58) by reverse transcription quantitative PCR. Initial levels and changes after one chemotherapy cycle were correlated with treatment outcomes in patient subsets. RESULTS: Relative serum RNU2-1f expression levels (REL) were elevated in lung cancer patients compared with patients with chronic lung disease and healthy controls (p 〈 0.0001). The area under the receiver operating characteristic curve for the complete data set (lung cancer vs. healthy) was 0.91 (95 % CI 0.87-0.95). By applying a REL of -4.505 as diagnostic cutoff (Youden's criterion), sensitivity and specificity reached 0.86 and 0.81, respectively. To determine the generalization error, in a subsampling study, sensitivity and specificity were estimated as 0.82 and 0.77 for the application to future, independent samples. High initial RNU2-1f REL were associated with shorter median survival in stage IIIB/IV disease (RNU2-1fhigh = 228 days/RNU2-1flow = 484 days; p = 0.009, log-rank test, HR1.43 95 % CI 1.23-1.66). Multivariate analysis confirmed RNU2-1f as an independent prognostic factor. Patients with subsequent RNU2-1f reduction had a trend toward better treatment outcome. CONCLUSIONS: Serum RNU2-1f may serve as a biomarker for lung cancer detection, prognosis prediction and treatment monitoring.
    Type of Publication: Journal article published
    PubMed ID: 26687686
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  • 2
    Keywords: GROWTH ; CELL LUNG-CANCER ; PATHWAYS ; MUTATIONS ; sensitivity ; FUTURE ; THERAPIES
    Abstract: PURPOSE: Multiple investigational drugs are currently explored in cancer patient populations defined by specific biomarkers. This demands a new process of patient selection for clinical trials. PATIENTS AND METHODS: Starting January 1, 2012, preemptive biomarker profiling was offered at the West German Cancer Center to all patients with advanced non-small-cell lung (NSCLC) or colorectal cancer (CRC), who met generic study inclusion criteria. Tumour specimens were subjected to prespecified profiling algorithms to detect 'actionable biomarkers' by amplicon sequencing, in situ hybridisation and immunohistochemistry. The clinical course was closely monitored to offer trial participation whenever applicable. RESULTS: Within 12 months, 267 patients (188 NSCLC, 79 CRC) were profiled. Estimated additional cost for biomarker profiling was 219615.51 EUR excluding histopathology workup and administration. The most prevalent biomarkers in pulmonary adenocarcinoma were KRAS mutations (29%), loss of PTEN expression (18%), EGFR mutations (9%), HER2 amplification (5%) and BRAF mutations (3%), while the prevalence of ALK translocations and PIK3CA mutations was extremely low. In pulmonary squamous cell carcinoma FGFR1 amplifications were found in 15%, PTEN expression was lost in 20% and DDR2 was mutated in a single case. KRAS mutations (41%) predominated in CRC, followed by loss of PTEN expression (16%), PIK3CA (5%) and BRAF (5%) mutations. So far 13 patients (5%) have entered biomarker-stratified clinical trials. Therapeutic decisions for approved drugs were guided in another 45 patients (17%). CONCLUSION: Preemptive biomarker profiling can be implemented into the diagnostic algorithm of a large Comprehensive Cancer Center. Substantial investments in diagnostics and administration are required.
    Type of Publication: Journal article published
    PubMed ID: 23876834
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  • 3
    Keywords: CELL LUNG-CANCER ; GENE ; TUMORS ; BREAST-CANCER ; immunohistochemistry ; IN-SITU HYBRIDIZATION ; PHASE-II ; RECOMMENDATIONS ; PATHOLOGISTS ; KINASE MUTATIONS
    Abstract: OBJECTIVES: Pulmonary adenocarcinomas (ADC) can be sub-grouped based on dominant oncogenic drivers. EGFR mutations define an entity of metastatic ADC with favorable prognosis and high susceptibility to EGFR tyrosine kinase inhibition. In contrast, the clinical impact of additional ERBB family members in ADC is less defined. To this end we prospectively studied HER2 expression, gene amplification, and mutation in relation to outcome of patients with advanced or metastatic ADC. MATERIALS AND METHODS: Diagnostic tumor biopsies from 193 sequential patients with stage III/IV ADC were prospectively studied for HER2 expression by immunohistochemistry (IHC). Cases with IHC scores 2+ or 3+ were analyzed by HER2 chromogenic in situ hybridization (CISH), and sequencing of HER2 exons 20 and 23. Additional prospectively determined biomarkers included PTEN, cMET, pAKT, and pERK expression, KRAS, EGFR, BRAF and PIK3CA mutations, and ALK fluorescence ISH (FISH). RESULTS AND CONCLUSION: HER2-IHC was feasible in 176 (91.2%) cases. Of 53 (30%) cases with IHC scores 2+/3+, 45 (85%) could be studied by CISH and 34 (64%) by sequencing. The lower number of HER2-mutational analyses resulted from exhaustion of tumor tissue and DNA following mutational analysis of KRAS, EGFR, BRAF and PIK3CA. HER2 amplification was detected in 4 cases (2.3%), while no mutation was found. HER2 expression correlated with expression of pAKT and cMET. Expression of HER2 and pAKT was associated with favorable overall survival in stage IV disease. HER2-expressing ADC more frequently harbored KRAS mutations, while HER2 expression was absent in all 4 cases with BRAF mutation. HER2-IHC was not predictive of HER2 gene amplification or mutation, which both were rare events in prospectively studied patients with advanced or metastatic ADC. Expression of HER2 and pAKT define a population of patients with stage IV ADC with a distinct disease course, who could benefit from specifically tailored pharmacotherapies.
    Type of Publication: Journal article published
    PubMed ID: 25708529
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