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The digitalization of the field of pneumology in Germany has a slowed down dynamic in the ambulatory sector, although the inclusion of telemedicine and its subgroups telemonitoring and telenursing makes it possible to treat a broad group of patients outside the existing practice structures, even with the addition of apps and monitoring of inhalers. The possibility to create professional networks and to build up an intersectoral structure between the outpatient and inpatient areas is desired and technically possible. Here, the field of sleep medicine is leading, whereby the existing obstacles to the development of data protection, reimbursement structures, and company-neutral data networks must be overcome.

Purpose: MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adeno- and squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer. Experimental Design: We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-naïve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC. Results: Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio ≥2.0 or average gene copy number per nucleus ≥6.0 or ≥10% of tumor cells containing ≥15 MET copies). The remaining cases can be subdivided into intermediate- (6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations. Conclusion: MET amplification is not a mutually exclusive genetic event in therapy-naïve non–small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors. Clin Cancer Res; 21(4); 907–15. ©2014 AACR.

We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

We recently reported fibroblast growth factor receptor-type 1 (FGFR1) amplification to be associated with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. This makes FGFR1 a novel target for directed therapy in these tumors. To reproducibly identify patients for clinical studies, we developed a standardized reading and evaluation strategy for FGFR1 fluorescence in-situ hybridization (FISH) and propose evaluation criteria, describe different patterns of low- and high-level amplifications and report on the prevalence of FGFR1 amplifications in pulmonary carcinomas. A total of 420 lung cancer patients including 307 squamous carcinomas, 100 adenocarcinomas of the lung and 13 carcinomas of other types were analyzed for FGFR1 amplification using a dual color FISH. We found heterogeneous and different patterns of gene copy numbers. FGFR1 amplifications were observed in 20% of pulmonary squamous carcinomas but not in adenocarcinomas. High-level amplification (as defined by an FGFR1/centromer 8 (CEN8) ratio ≥2.0, or average number of FGFR1 signals per tumor cell nucleus ≥6, or the percentage of tumor cells containing ≥15 FGFR1 signals or large clusters ≥10%) was detected at a frequency of 16% and low-level amplification (as defined by ≥5 FGFR1 signals in ≥50% of tumor cells) at a frequency of 4%. We conclude that FGFR1 amplification is one of the most frequent therapeutically tractable genetic lesions in pulmonary carcinomas. Standardized reporting of FGFR1 amplification in squamous carcinomas of the lung will become increasingly important to correlate therapeutic responses with FGFR1 inhibitors in clinical studies. Thus, our reading and evaluation strategy might serve as a basis for identifying patients for ongoing and upcoming clinical trials.

Purpose Positron emission tomography (PET) with both 2′-deoxy-2′-[18F]fluoro-d-glucose (FDG) and 3′-[18F]fluoro-3′-deoxy-l-thymidine (FLT) was evaluated with respect to the accuracy of early prediction of nonprogression following erlotinib therapy, independent from epidermal growth factor receptor (EGFR) mutational status, in patients with previously untreated advanced non–small-cell lung cancer (NSCLC). Patients and Methods Thirty-four patients with untreated stage IV NSCLC were evaluated in this phase II trial. Changes in FDG and FLT uptake after 1 (early) and 6 (late) weeks of erlotinib treatment were compared with nonprogression measured by computed tomography after 6 weeks of treatment, progression-free survival (PFS), and overall survival (OS). Results Changes in FDG uptake after 1 week of therapy predicted nonprogression after 6 weeks of therapy with an area under the receiver operating characteristic curve of 0.75 (P = .02). Furthermore, patients with an early metabolic FDG response (cutoff value: 30% reduction in the peak standardized uptake value) had significantly longer PFS (hazard ratio [HR], 0.23; 95% CI, 0.09 to 0.59; P = .002) and OS (HR, 0.36; 95% CI, 0.13 to 0.96; P = .04). Early FLT response also predicted significantly longer PFS (HR, 0.31; 95% CI, 0.10 to 0.95; P = .04) but not OS and was not predictive for nonprogression after 6 weeks of therapy. Conclusion Early FDG-PET predicts PFS, OS, and nonprogression after 6 weeks of therapy with erlotinib in unselected, previously untreated patients with advanced NSCLC independent from EGFR mutational status.

1589 Background: The incidence of SPLC in Germany was reported to be 1.2 per 100,000 inhabitants in 2007 and the prevalence of second primary cancers reported by the US International Cancer Institute's Surveillance, Epidemiology and End Results Program has more than doubled over the last 25 years. Recently there has been tremendous progress in the ability to detect driver mutations in lung cancer and large studies presented the frequencies of driver mutations in unselected patient populations. We conducted an association study of known genetic driver events and clinical characteristics with the occurence of SPLC. Methods: Within the Network Genomic Medicine Lung Cancer, a local molecular screening network encompassing hospitals and office-based oncologists in the catchment area of the Center for Integrated Oncology Köln Bonn, we retrospectively reviewed the medical records of 375 molecularly annotated NSCLC patients for their SPLC status and clinical characteristics (age at diagnosis, histology, sex, smoking status). Molecular analysis for lung adenocarcinoma included the EGFR, ALK, BRAF, KRAS and PIK3CA status and for squamous cell lung cancer the FGFR1 and PIK3CA status. Results: 84 of 375 (22,4%) patients were SPLCs. The median age of SPLC diagnosis was 70 yrs. (Range 53 - 85 yrs.) and differed significantly from the rest of the population with a median age of 65 yrs. (Range 28 - 86 yrs.). The frequency of SPLCs was not significantly different between males and females (p = 0,259). In univariate logistic regression analysis active and former smoking, positive PIK3CA mutation and FGFR1 amplification status as well as age were significantly associated with the occurrence of SPLC. In a multivariate logistic regression analysis including the variables mentioned above only PIK3CA mutations (OR 9,48 95% CI 1,83 - 49,1) (p = 0,007) and age (OR 1,06 95% CI 1,03 - 1,1) (p = 0,015) could be confirmed to be independent prognosticators for the occurrence of SPLCs. Conclusions: The occurrence of SPLC was associated with age and PIK3CA mutations in our study population. Further comprehensive investigations on this topic are needed to confirm our findings and to further understand the association between mutation status and SPLCs.

CRA10529 Background: Personalized treatment of genetically stratified subgroups has the potential to substantially improve outcome in NSCLC. A major challenge now is to implement high-quality molecular diagnostics and personalized treatment strategies in routine clinical practice also outside of highly specialized academic centers. Methods: We have established a molecular screening network in the catchment area of our comprehensive cancer center encompassing about 2.5 million inhabitants in March 2010 after review of the local ethics committee (10-242). Lung adenocarcinoma (AD) was screened centrally for ALK translocations, mutations in KRAS, EGFR, BRAF and PIK3CA and for amplification of ERBB2. Squamous cell carcinoma (SQ) was analyzed for FGFR1 amplifications. Results: 2032 NSCLC samples were acquired of which 1782 in the Cologne-Bonn area indicating a capture rate of 60-70% of all NSCLC samples in the area. Material was suitable for molecular analysis in 77%. Distribution of histological subtypes was as expected (AD 63.4%, SQ 26.7, large cell carcinoma 1.4%, adenosquamous cell carcinoma 1.8%, carcinoid 0.1%, NSCLC NOS 6.7%. In AD the following frequencies of genetic lesions were detected: KRAS (32%), EGFR (13%), ALK (3%), BRAF (2%), PIK3CA (2%), ERBB2 (2%). EGFR mutations were highly enriched in the lepidic and micropapillary subtype of AD (30-32%), whereas the solid subtype only harboured a very small amount of the tested oncogenic lesions. In SQ FGFR1 amplification was detected in 78/500. Overall 40% of all NSCLC samples harboured potentially tractable oncogenic lesions. All patients with ALK translocations received crizotinib when clinically indicated. 75% of the stage IIIB/IV patients with activating EGFR mutations received EGFR-TKI treatment. In addition, clinical trials have been initiated to provide personalized treatment options to all patients with tractable genetic lesions. Conclusions: High-quality molecular diagnostics and identification of patients for personalized treatment approaches is feasible in daily clinical routine for the majority of diagnostic samples also in a non-academic setting.

10526 Background: PIK3CA mutations are a rare oncogenic event of potential therapeutic relevance in NSCLC. Here we report frequency and characteristics of patients with PIK3CA mutated lung tumors. Methods: Patients with NSCLC and PIK3CA mutations were identified within our regional Network for Molecular Screening in Lung Cancer. We further analyzed the presence of BRAF, KRAS, EGFR mutations as well as ALK translocation, ERBB2 and FGFR1 amplifications in PIK3CA mutated samples. Clinical data on age, sex, TNM classification and tumor stage, histological type, grading, overall survival, smoking status, comorbidity, BMI and secondary malignancies were retrieved from clinical charts in accordance with the local ethics committee. Results: PIK3CA mutations were detected with a frequency of 3.7% (24% exon 20,76% exon 9) in 1000 patients. Histologically 32% were defined as squamous cell carcinoma, 48% as adenocarcinoma and 18% other histological subtypes or NSCLC-NOS. Exon 9 mutations were present in the acinar and lepidic subtype, whereas exon 20 mutations were seen in the papillary and solid subtype. Cooccuring genetic lesions were observed in 16% (mutations in KRAS=2, EGFR=1, BRAF=1; FGFR1 amplification=2). 14 were female, 23 male with a mean age of 69 years. 21 of these patients were further clinically annotated. 11 patients presented with stage IIIb/IV eligible for palliative treatment and 10 stage I – IIIa eligible for surgical therapy +/- adjuvant therapy. All but 1 patient were smokers with an average BMI of 26,2kg/m2 with a typical high load of comorbidity mainly of cardiovascular diseases, 8 of 21 patients showed prior malignancies in their medical history. The median overall survival within this population has not been reached yet. Conclusions: Screening for PIK3CA mutations is feasible. A high proportion (38%) of patients with PIK3CA mutated lung cancer have prior malignancies and show a high load of comorbidity. Furthermore PIK3CA mutations are not exclusive to KRAS, EGFR or BRAF mutations or FGFR1 amplifications. Successful identification of patients with oncogenic lesions in lung cancer in a screening network might allow future personalized treatment of these patients.

1533 Background: FGFR1 amplifications have been described as a promising oncogenic target in squamous cell lung cancer. Here we aimed at describing the clinical characteristics and natural history of FGFR1amplified squamous cell lung cancer patients. Methods: From 01/2011 to 01/2012 we screened 553 squamous cell lung cancer patients in our Network for Molecular Screening of Lung Cancer for the presence of FGFR1 amplifications by FISH analysis in accordance with the local ethics committee. FGFR1 was defined as amplified if the ratio of FGFR1 copies to centromeric copies was above 2 or if more than 50% of tumor cells showed 5 copies or if more than 15% of tumor cells demonstrated clusters of FGFR1. Clinical data were collected by extracting information from medical records, the local cancer registry and by questioning treating physicians and patients. Results: FGFR1FISH analysis could be performed in 95% of the cases and was amplified in 16%. Of the amplified cases 75 % were male and 25% female without significant enrichment for male or female. The median age of the patients at diagnosis was 67 yrs (range 46 - 82). Stage at presentation was: 16% I; 17.3% II; 26.7% IIIa, 40% IIIb/IV. 97,3% of the patients were former or active smokers with a median of 40 pack years. The median progression free survival of patients with stage IIIb/IV disease was 11 months (95% CI 8-14; n=14). The median overall survival was not yet reached after a median follow-up time of 14 months (95% CI 11 - 17; n=24). We further screened for co-existing genetic lesions such as mutations in EGFR, BRAF, KRAS, PIK3CA as well as translocations of ALK and amplifications of ERBB2. Two patients demonstrated co-occurring PIK3CA mutations and one a BRAFmutation. Conclusions: Screening for FGFR1 is feasible under routine clinical conditions. By implementation of a regional molecular screening network the ability to screen for FGFR1 amplification was successfully expanded to non-academic centers and private practices. FGFR1 amplifications in squamous cell cancer of the lung are frequent (16%) and associated with smoking history. Screening for FGFR1 might pave the way for the application of new FGFR1 directed targeted drugs in squamous cell lung cancer.