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Background: Inhibiting both IGF-1R and IR signaling may be required to disrupt the malignant phenotype regulated by the receptor family. BMS-754807 is a potent and selective reversible inhibitor of IGF-1R/IR family kinases (IGF-1R, IR; Ki Methods: CA191002 is an ascending multiple-dose study to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of BMS-754807 in subjects with solid tumors. Dosing occurs daily 2 hours after a light breakfast and is followed by a 4 hour fast. PD effects on IR are studied by assessments of plasma glucose, insulin and C-peptide. 2-deoxy-2-[18F] fluoro-D-glucose (FDG)- and 3′-deoxy-3′-[18F] fluorothymidine (FLT)-PET imaging is performed both as imaging markers for PD and to assess anti-tumor activity. Results: Sixteen subjects have been treated at daily doses of 4, 10, 20, 30 or 50 mg. No dose limiting toxicities have been observed and dose escalation is ongoing. Duration of dosing was between 8 and 197 days. Preliminary analysis shows dose related increases of plasma glucose, insulin and C-peptide at 2 hours post-dose (Table 1). The range [median] of plasma glucose at all time points was 68 –187 [95], 50 – 168 [103] and 54 –333 [124] mg/dL in subjects treated at the 4, 10 and 20, and 30 and 50 mg dose levels, respectively. 65 PET scans have been collected from 14 subjects. Preliminary analysis shows that 1 subject with osteosarcoma and 1 subject with adenoid cystic carcinoma achieved 57 and 28 % reduction of tracer uptake, respectively, on FLT-PET by D12. Both had stable metabolic disease on FDG-PET by D12 and D56. Conclusion: PD effects of IR inhibition differentiate BMS-754807 from IGF-1R specific agents. PET results suggest anti-tumor activity. Future analysis of PD effects, PET imaging data, safety information and response assessments will provide the basis for a rational selection of subjects and a dose or dose range to be further explored. Dose level (number of subjects) Plasma glucose [mg/dL] D1 and 8 2 h post-dose range [median] Insulin [µU/mL] D1 and 8 2 h post-dose range [median] C-peptide [ng/mL] D1 and 8 2 h post-dose range [median] 4 mg (3) 77 – 101 [94] 2 – 82 [12.5] 0.8 – 7 [1.8] 10 and 20 mg (7) 90 – 144 [97] 27 – 251 [58] 3 – 18 [4.6] 30 and 50 mg (6) 110 – 200 [137] 120 – 361 [210] 5 – 17 [12.1] Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A109.

BackgroundA recurrent somatic mutation, E17K, in the pleckstrin homology domain of theAKT1gene, has been recently described in breast, colorectal, and ovarian cancers. AKT1 is a pivotal mediator of signalling pathways involved in cell survival, proliferation and growth. The E17K mutation stimulates downstream signalling and exhibits transforming activityin vitroandin vivo.FindingsWe developed a sensitive high resolution melting (HRM) assay to detect the E17K mutation from formalin-fixed paraffin-embedded tumours. We screened 219 non-small cell lung cancer biopsies for the mutation using HRM analysis. Four samples were identified as HRM positive. Subsequent sequencing of those samples confirmed the E17K mutation in one of the cases. A rare single nucleotide polymorphism was detected in each of the remaining three samples. The E17K was found in one of the 14 squamous cell carcinomas. No mutations were found in 141 adenocarcinomas and 39 large cell carcinomas.ConclusionTheAKT1E17K mutation is very rare in lung cancer and might be associated with tumorigenesis in squamous cell carcinoma. HRM represents a rapid cost-effective and robust screening of low frequency mutations such asAKT1mutations in clinical samples.

7508 Background: In this study we tested the ability of our serum mass spectrometry classifier of clinical benefit from gefitinib to classify pre-treatment sera and plasma samples from non-small cell lung cancer (NSCLC) patients treated first line with erlotinib in ECOG E3503. Methods: Pretreatment serum and plasma samples were available from 73 of the 96 previously untreated advanced NSCLC patients treated with single agent erlotinib on ECOG protocol 3503, 13 subjects had only serum samples, and 10 had only plasma samples. All of these samples analyzed in replicate by MALDI mass spectrometry (MS). A prediction algorithm we established based on a training cohort of 139 patients treated second or third line with gefitinib was used to classify these patients for survival and time to progression, and results obtained from serum and plasma were compared when both were available Results: We found that the signals for the 8 distinct mass-to-charge (m/z) features used in our classifier were highly concordant between serum and plasma samples from the same patient, and that there was no difference in the classification of the patients between serum and plasma when both were available. Therefore we classified all 96 patients using serum if available, and plasma if not. The classification algorithm very successfully classified patients into groups with good and poor survival (median survival of 306 days vs 107 days, p = 0.0007). With the available follow-up, the time to progression was also statistically significant in this group (p = 0.007, data not shown). In a Cox multivariate analysis including the most significant univariate parameters PS (0 vs. 1 vs 2), number of involved sites (=3 vs >3) and prior weight loss ( No significant financial relationships to disclose.

7004 Background: Assessment of epidermal growth factor receptor (EGFR) gene copy number, mutational status, and protein levels may predict response and possibly survival following treatment with EGFR tyrosine kinase inhibitors, but all these methods require tumor tissue, highlighting the need for a non-invasive predictive test. We evaluated the ability of MALDI-TOF MS profiling of serum to predict which patients (Pts) with NSCLC were likely to benefit from gefitinib treatment. Methods: Serum from Pts with NSCLC, collected prior to treatment with gefitinib, was subjected to MALDI-TOF MS using Voyager DE-STR or DE-PRO instruments. Replicate mass spectra obtained at two institutions were submitted to a third party for processing (background subtraction, noise estimation, normalization, spectral alignment and peak identification) and selection of discriminating mass/charge (m/z) values from a training cohort of 70 Caucasian Pts. The predictive capability of the profile was then assessed in independent cohorts of NSCLC Pts. Results: Intra- and inter- laboratory reproducibility of MALDI spectra were excellent. A set of 11 m/z values (mass range 5 - 12.5 kDa) predictive of clinical benefit were identified in the training cohort and confirmed by leave-one-out cross validation. Spectra from 19/70 Pts in the training cohort were unclassifiable. For the remaining 51 Pts the algorithm discriminated groups more or less likely to benefit with respect to time to progression (median 3.0 vs. 1.5 mo., p = 0.0325) and overall survival (median 14.6 vs. 2.3 mo., p = 0.0128). Validation was performed in an independent cohort consisting of serum from 69 Japanese Pts. Spectra from 13/69 Pts were unclassifiable. For the remaining 56 Pts it was possible to identify a group with superior time to progression (median 14.8 vs. 2.1 mo., p = 0.0012) and overall survival (median 19.1 vs. 7.9 mo., p = 0.0102). Conclusions: MALDI-TOF MS of pretreatment serum may aid with the identification of subsets of NSCLC Pts that will benefit from treatment with gefitinib. This algorithm is currently being evaluated in an expanded cohort of Pts receiving gefitinib treatment and in Pts treated with erlotinib. [Table: see text]

In this survey of union membership in the twentieth century, principal attention is paid to the white-collar component of the labor force. White-collar jobs have been increasing at a much more rapid rate than have manual jobs, a trend which promises to continue into the future. It is in this area that the greatest potential for future union organization exists, yet it is here that unions have experienced the least success in attracting members. (Author's abstract courtesy EBSCO.)

In this article the author offers some comments on "The Authority Structure of the School: System of Social Exchange" by James Ander son, which appeared in the spring issue of this journal. The author is Research Associate and Director, White Collar Studies, Industrial Re lations Center, University of Chicago.

Public education has probably never been the subject of so much discussion as it is today. However, an observer from afar might be puzzled by the seeming lack of attention paid to the voice of teachers in this discussion and by their apparently low status in the education scheme. He might conclude that teachers are taken for granted and that they, in turn, take for granted the education framework devised by others. The issue of the role of teachers in education brings into question the arrangements under which teachers work. Work arrangements are the complex of factors that affect how the members of an occupation participate in their work process. Examples of such factors are the type of tenure, the system of authority in the work process, the methods by which the terms of employment are decided, and the nature of occupational organization. The wage system, peonage, and slavery are broad examples of work arrangements. If anyone were to suggest that teachers provide their services under arrangements similar to slavery, there would undoubtedly be a great hue and cry. And teachers would join in strenuously. Of course, no serious person would propose such an absurdity. But even if the work arrangements in our school systems are less extreme than slavery, it may be worthwhile to examine the overall conditions under which teachers do provide their services. For the teaching profession is important to education, comprising its

Transforming rearrangements of the ALK (anaplastic lymphoma kinase) gene have recently been described in non-small cell lung cancer (NSCLC). The most common rearrangement arises from an inversion in the short arm of chromosome 2 that creates a fusion between the 5′ portion of the EML4 (echinoderm microtubule-associated protein-like 4) gene and the 3′ portion of the ALK gene. At least seven ALK gene rearrangement variants have been described involving different EML4-ALK breakpoints or rarely other non-EML4 fusion partners. ALK rearrangements may be readily identified in tumor tissue by reverse transcription-polymerase chain reaction or fluorescent in situ hybridization. Although ALK gene rearrangements affect only about 4% of all lung cancers, they are more frequent in adenocarcinomas, in never or light smokers, and seem almost mutually exclusive with activating EGFR or KRAS mutations. Promising results seen in patients with NSCLC containing fluorescent in situ hybridization-detected ALK rearrangements treated on a phase I study with PF02341066, an oral ALK inhibitor, indicate that ALK represents a new therapeutic target in this molecularly defined subset of NSCLC.

Many aspects of the clinical and pathological phenotype of non-small cell lung cancer (NSCLC) harboring rearrangements in the anaplastic lymphoma kinase (ALK) gene have been characterized following the description of the EML4-ALK fusion gene in NSCLC in 2007.1,2 These tumors most frequently occur in younger, never or light smokers with adenocarcinoma, are almost always mutually exclusive with EGFR or KRAS mutations, and demonstrate exquisite sensitivity to treatment with the ALK inhibitor crizotinib.3 However, there are few published data regarding the natural history and clinical outcomes of ALK-positive NSCLC. Two reports in this issue of the Journal of Thoracic Oncology, conducted in different patient populations using different methods to detect ALK rearrangements, provide apparently conflicting conclusions about the prognostic significance of ALK gene rearrangements in NSCLC and raise questions about the optimal method to detect ALK gene rearrangements in clinical samples. In the first study, Wu et al. performed a retrospective analysis using reverse transcription polymerase chain reaction (RT-PCR) to detect ALK gene rearrangements in cell pellets derived from malignant pleural effusions in 116 EGFR wild-type, Taiwanese patients with stage IIIB/IV NSCLC. Thirty-nine patients (34%) were found to have ALK gene rearrangements and, in contrast to other studies, these patients did not differ from ALK-negative patients with respect to age or smoking history. Wu et al. observed better median survival in the ALK-positive patients compared with the EGFR wild-type, ALK-negative patients (14.7 versus 10.3 months, p 0.009). In the second study, Yang et al. screened 300 never smokers from the Mayo Clinic Lung Cancer Cohort with a two-staged process involving immunohistochemistry (IHC) using the commercially available monoclonal ALK1 antibody (Dako, Capinteria, Ca) followed by fluorescence in situ hybridization (FISH) using break-apart probes (Vysis, Des Plaines, IL). In this cohort of predominantly early-stage tumors (191/300 stage I/II, 62/300 stage II, and 47/300 stage IV), 22 patients (8.2%) were determined to be ALK-positive by FISH. No overall survival data are presented, but using a composite end point of 5-year progression-free survival (PFS) and recurrence-free survival, adjusted for stage and treatment modality, Yang et al. found inferior outcomes in the ALK-positive cohort, with a twofold increase in the risk of experiencing disease progression or recurrence within 5 years in ALK-positive compared with ALK-negative patients. How do these articles with apparently contradictory findings fit in with what is known about clinical outcomes in this patient population? Of note, assessment of the predictive and prognostic significance of ALK gene rearrangements in NSCLC is limited by the fact that, with the exception of one prospective, single-arm study,3 the published data are limited to relatively small retrospective studies. Furthermore, the possibility of ascertainment bias cannot be excluded because of potential differences in the populations

A 32-year-old Chinese female never smoker presented with persistent cough in June 2009, and imaging studies revealed a right hilar mass. An endobronchial biopsy of the tumor revealed a moderately differentiated mucinous adenocarcinoma that was cytokeratin 7 (CK7) positive, CK20 negative, transcription tissue factor-1 (TTF-1) positive, and mucicarmine positive. Initial molecular analysis revealed the tumor to be both epidermal growth factor receptor and KRAS wild type. Her staging workup revealed metastasis to the liver and brain. She underwent stereotactic radiosurgery of her brain metastases that was followed by six cycles of cisplatin/pemetrexed/bevacizumab combination chemotherapy followed by bevacizumab maintenance therapy, with a partial response to treatment. In November 2009, she decided to undertake a treatment holiday for 3 months. By February 2010, however, her disease had progressed, and she commenced single-agent erlotinib treatment but had documented disease progression after 6 weeks. She was referred by her treating oncologist for possible enrollment into the phase I crizotinib trial because her clinical profile—young age, adenocarcinoma histology, never-smoking status, and most importantly her tumor is wild type for epidermal growth factor receptor and KRAS—fits the profile of an anaplastic lymphoma kinase (ALK)-positive patient with non-small cell lung cancer (NSCLC).

Background Novel therapeutic agents recently introduced for the treatment of cancer have several unusual side effects. An increased incidence of renal cystic lesions, often with features concerning for malignancy or infection, has been reported in patients with anaplastic lymphoma kinase (ALK) - rearranged advanced non-small cell lung cancer (NSCLC) treated with Crizotinib. Many of these lesions undergo spontaneous resolution despite developing complex features on imaging. We assess the incidence and patterns of evolution of Crizotinib Associated Renal Cysts [CARCs] at our institute and provide histopathology correlation of their benign nature. Methods A retrospective analysis of renal lesions in computerised tomography (CT) scans of 35 patients with advanced ALK-rearranged NSCLC who had been prescribed crizotinib at our institution was performed by three radiologists, who analysed the evolution of these lesions, particularly for pre-defined significant and complex changes. Results Of 26 patients eligible for this analysis, 4 (15%) had cysts at baseline that remained stable on crizotinib treatment while 11(42%) developed significant change in 28 renal cysts. Commonest pattern of cyst evolution was enlargement from baseline followed by spontaneous regression (17/28 lesions) while other patterns noted were stable lesions, regression from baseline and ongoing enlargement. The median maximum size reached was 23 mm (range 9 – 67 mm) after a median of 178 days (160 to 1342) on crizotinib. Complex change occurred in 12 cysts, in 7/26 (27%) patients and within 60 days of starting Crizotinib in 10 cysts. Imaging features were falsely concerning for malignancy or abscess in 4/26 patients. Conclusion Most CARCs resolve spontaneously, or have a benign evolution despite enlargement and other features concerning for malignancy or infection on imaging. This unusual manifestation of chemotherapy should be recognised, particularly by radiologists, so that inappropriate treatment decisions are avoided.

Because of the high rate of distant disease recurrence, the 5-year survival of patients who have undergone complete surgical resection of localized non-small-cell lung cancer (NSCLC) is approximately 50%. Initial results from early studies of adjuvant postoperative chemotherapy reported an adverse effect of alkylating agent and older chemotherapy regimens on survival. Cisplatin-based combinations were the first to show a survival advantage. A 1995 meta-analysis of these studies suggested a 13% reduction in the hazard ratio for death (HR = 0.87), leading to a 5% survival benefit at 5 years. Still, these trials involved limited numbers of patients (N = 1,394), and the results failed to reach statistical significance (P = .08). Of the five largest subsequent randomized trials of platinum-based adjuvant therapy, three showed a significant survival advantage. Although it is impossible to determine the reasons for the differing outcomes of these studies, several key features distinguish them, and the data suggest that medically fit patients with resected stage IB or II NSCLC should be offered chemotherapy with a platinum/new drug combination.