cribed mutations and have characterized their 14192894 response to TKI treatment. Of specific note is the p.D770GY mutation, which 
was found in two patients, with different response. The first of these patients had a combination of p.D770GY and a p.G719C mutation while the second had only a p.D770GY mutation. The first patient responded to EGFR TKI and remains disease free after 15 BKM 120 price months while the patient without the secondary mutation had progressive disease diagnosed at 4 weeks. Previously 2 cases of this mutation were described without information on tumor response. Our data suggest that the p.G770GY mutation does not provide benefit for EGFR TKI treatment. Furthermore, we demonstrated that also patients with one of the other 4 rare EGFR mutations had no benefit from EGFR-TKI. Small tumor samples mainly from bronchoscopic or transthoracic core biopsies may be a problem for adequate mutation testing. We identified causes why mutational analysis at our lab was not possible in 17% of patients. This was either due to insufficient number of tumor cells or due to insufficient DNA quality highlighting the need for adequate tumor tissue selection for mutational analysis. Retrospective studies in which long- term archived paraffin embedded tissue was used to determine EGFR status showed a low proportion of adequate tumor tissue available. One way to obtain more tumor cells is by repeated biopsies or cryobiopsies. New technological developments are far more sensitive than previously, allowing fewer tumor cells both qualitatively 10742299 and quantitatively required for detecting mutations. However, regarding tumor heterogeneity, this increased sensitivity harbors an increased risk of sampling errors and detection of minor clones that may be less relevant for therapy. A study showed that about two thirds of all somatic mutations seemed not to be detectable across every tumor region. EGFR mutations occurred most often in TTF-1 positive adenocarcinoma. Two recent studies showed this cell lineage association. Functionally, TTF-1 induced ROR-1 is necessary to sustain the EGFR signaling pathway in lung adenocarcinoma cell lines. We identified the preference of EGFR mutant tumors to spread to intrapulmonary and to both the vertebra and other bone localizations. This contrasts with a study by Doebele et al, who observed only a preference for hepatic metastatic spread in EGFR mutant tumors.In contrast, we observed the typical miliary 6 EGFR/KRAS Mutation Status in Dutch NSCLC Patients pattern of tumors with EGFR exon 19 deletion as described previously. Our results for KRAS mutant tumors were as described previously by Doebele et al . In our population the outcome of patients with a KRAS mutation responded similarly to KRAS WT both with respect to chemotherapy and to EGFR TKI. Previously it was demonstrated that patients with KRAS wild type have a better outcome than patients with KRAS mutations when treated with an EGFR TKI. Other studies showed the presence of KRAS mutations in lung cancer to be indicative of worse outcome regardless of the treatment they received. In the TITAN study, there was some evidence for a higher risk of death in KRAS mutant tumor patients treated with erlotinib compared to chemotherapy but there was no elevated risk of tumor progression. In our study, we did not pool the EGFR mutation positive patients with the EGFR/KRAS WT when comparing these patients with KRAS mutant patients. As patients with EGFR mutations tend to have better outcomes t
