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B. Solomon



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    MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO21.10 - Serial monitoring of plasma EGFR T790M levels and evaluation of EGFR mutational status in matched tissue and plasma from NSCLC patients treated with CO-1686 (ID 2498)

      11:25 - 11:30  |  Author(s): B. Solomon

      • Abstract
      • Presentation
      • Slides

      Background
      Background: We explored the minimally-invasive detection of EGFR mutations in circulating free DNA from plasma and studied the concordance of EGFR mutation status between matched plasma and tumor tissue in a cohort of newly diagnosed or relapsed patients with advanced NSCLC. CO-1686 is an oral, potent, small-molecule irreversible tyrosine kinase inhibitor that selectively targets mutant forms of EGFR, including T790M and the common initial activating mutations, while sparing wild-type EGFR. Promising clinical activity has recently been reported from an on-going Phase I/II trial.

      Methods
      Methods: Matched tumor tissue and blood from 80 Stage IIIB/IV NSCLC patients, 41 treated with CO-1686, were tested using two allele-specific PCR assays, the cobas® EGFR FFPET and cobas® EGFR blood tests. Each test detects 41 mutations in EGFR, including the T790M resistance mutation, exon 19 deletions and L858R. We also used BEAMing, a highly quantitative and sensitive technology based on digital PCR, to assess a subset of 18 patients treated with CO-1686. BEAMing was compared to cobas analysis at baseline, and also used to serially monitor plasma EGFR mutation levels in response to CO-1686.

      Results
      Results: Using tissue as reference, the positive percent agreement between tissue and plasma was 76% (44/58) for activating mutations and 63% (17/27) for T790M. The cobas® EGFR blood test identified two patients with T790M mutations in plasma that were not detected in the corresponding tumor biopsy—likely because of tumor heterogeneity. The M1a/M1b status was known for 63 EGFR mutation-positive patients. Of the 44 with extrathoracic metastatic disease (M1b), 38 were found to have an activating mutation in plasma (86%). Conversely, only 53% (10/19) of EGFR mutation-positive patients with intrathoracic metastatic disease (M1a) had detectable activating mutations in plasma (p = 0.0081). For the 18 patients profiled by BEAMing, the overall percent agreement between BEAMing and the cobas® EGFR blood test was 94% (17/18) for T790M and 83% (15/18) for activating mutations. Nine of the 18 patients had detectable baseline plasma T790M levels, and several patients treated with CO-1686 had an initial decrease in plasma T790M by BEAMing.

      Conclusion
      Conclusions: Using the cobas® EGFR blood test, a high proportion of EGFR mutations identified in tissue were also detected in plasma. Mutations were more readily detectable in the plasma of patients with M1b rather than M1a disease. These findings suggest that the cobas® EGFR blood test and BEAMing can be useful tools for the non-invasive assessment and monitoring of EGFR mutations in NSCLC patients.

      EGFR mutation Evaluable patients Patients with tissue mutations* Patients with plasma mutations** Patients with same mutation detected in tissue and plasma Positive Percent Agreement***
      L858R, del19, S768I, G719X, or ex20ins 80 58 44 44 76%
      T790M 80 27 19 17 63%
      * identified by the cobas® EGFR tissue test
      ** identified by the cobas® EGFR blood test
      ***agreement of blood and tissue mutation-positive results with tissue as reference; although tissue is reference, some mutations may be missed due to tumor heterogeneity

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    O04 - Molecular Pathology I (ID 126)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O04.01 - Identification of CD74-NRG1, a new recurrent fusion gene in invasive mucinous lung adenocarcinomas of never smokers (ID 4022)

      10:30 - 10:40  |  Author(s): B. Solomon

      • Abstract
      • Presentation
      • Slides

      Background
      Lung adenocarcinoma (AD) of patients who have never smoked frequently bear targetable genome kinase alterations, such as EGFR mutations and translocations affecting ALK, ROS1, and RET genes. These mutations correlate with kinase inhibitor sensitivity in mouse models or in patients. Unfortunately, therapeutically relevant kinase alterations are not present in all lung cancer specimens. Thus, additional genome alterations need to be discovered in order to provide a therapeutic opportunity for the remaining patients.

      Methods
      We collected a cohort of 25 AD specimens of never smokers lacking mutations in KRAS or EGFR, in which we performed transcriptome sequencing with the aim of identifying new oncogenic driver genes.

      Results
      We were able to identify known kinase fusions affecting ALK, ROS1 and RET genes in 3 cases each. Moreover, we detected one sample carrying a novel chimeric transcript fusing the first six exons of CD74 to the EGF-like domain of the NRG1 III-β3 isoform, leading to the expression of its EGF-like domain in an otherwise NRG1-negative tumor tissue. The fusion gene was further detected in four additional cases out of 94 pan-negative* ADs of never smokers. In total, all 5 cases were identified in stage I invasive mucinous lung adenocarcinomas (IMA) of never smoker females. This tumor type frequently presents with multifocal unresectable disease, for which no effective treatment has been yet established. IMA is highly associated with KRAS mutations; indeed, out of 15 IMA analysed, 6 carried a KRAS mutation (40%), and 4 the CD74-NRG1 fusion (27%). Given the fact that NRG1 signals through ERBB3 and ERBB4 receptors, we aimed to determine which receptor CD74-NRG1 provides the ligand for. We observed that ERBB4 was not expressed in the index case, while ERBB3 was relatively highly expressed and this expression also correlated with a positive phospho-ERBB3 (p-ERBB3) signal in the tumoral tissue of all 5 CD74-NRG1 positive cases. In order to test if this phosphorylation of ERBB3 was statistically significant, we stained a cohort of 241 ADs and found that p-ERBB3 was only positive in 6 of them (p-value<0.0001). Additionally, although both EGFR and ERBB2 were expressed in the index case, only ERBB2 expression correlated with a p-ERBB2 positive signal. These data suggest that CD74-NRG1 might provide the ligand for ERBB3, which may form heterodimers with ERBB2, since ERBB3 is devoid of intrinsic kinase activity and cannot support linear signaling in isolation. This is in line with previous studies showing that NRG1 induces an oncogenic signal through ERBB2-ERBB3 heterodimers engaging the PI3K-AKT pathway. This was further supported by the activation of the PI3K-AKT, but not the MAPK pathway, in CD74-NRG1 transduced H2052 lung cells, after 24h starvation. *pan-negative: EGFR, KRAS, ALK, HER2, BRAF, ROS1 and RET wild-type

      Conclusion
      Altogether, these data shows that CD74-NRG1 is a new recurrent oncogenic fusion gene, highly associated with IMA of never smokers. It also suggests that CD74-NRG1 fusion protein signals through the ERBB2-ERBB3 receptors complex leading to the activation of the PI3K-AKT pathway, providing a therapeutic opportunity for a tumor type with, so far, no effective treatment.

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    P1.13 - Poster Session 1 - SCLC (ID 200)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.13-002 - Prognostic Value of 18F-fluorodeoxyglucose Uptake in Small Cell Lung Cancer Patients Treated with Concomitant Chemo-radiotherapy or Chemotherapy alone (ID 1277)

      09:30 - 09:30  |  Author(s): B. Solomon

      • Abstract

      Background
      There is some evidence that the standard uptake value (SUV) measured using 18F- fluorodeoxyglucose positron emission tomography ([18]FDG-PET) in patients with non-small cell lung cancer (NSCLC) may be prognostic for survival. Small cell lung cancer (SCLC) clinically differs from NSCLC by its rapid proliferation and is staged as either limited disease (LD) defined as disease confined to one hemithorax and the regional lymph nodes or extensive disease (ED) which is disease that has spread beyond this. There is much less information available on the potential prognostic value of the SUV obtained during [18]FDG-PET scanning in SCLC. This study thus aims to explore whether SUV can be effective in the prognostic stratification of SCLC patients with LD and ED.

      Methods
      Retrospective study of patients diagnosed with SCLC who underwent a pre-treatment 18FDG-PET scan between 1999 – 2008 at the Peter MacCallum Cancer Centre and 2004 -2011 at the Austin Hospital. Patients with LD were treated with radical concomitant chemo-radiotherapy and those with ED treated with chemotherapy alone. Maximum and mean SUVs were retrieved, and survival of patients measured. The correlation between SUV and other patients’ clinicopathological factors, including age, sex, performance status, weight loss and tumour stage (TNM) were also explored.

      Results
      Thirty-six eligible patients were identified, with a median follow-up of 14 months (range, 3-103 months). There were 23 males and 13 females. The median age was 69 years (55-84 years). Twenty patients had LD and 16 had ED. Thirteen patients had stage IV disease and 10 patients each had stage IIIA and IIIB disease (3 patients were unable to be staged according to TNM classification system). Higher TNM stage was associated with higher SUVmax (r~s~=0.37, p=0.036) but not with SUVmean (r~s~=0.30, p=0.086). There was no evidence of a significant association between clinicopathological factors with SUVmax in patients with LD and ED, except for age in patients with ED. Increasing age was associated with higher SUVmax (r~s~=0.72, p=0.002) and higher SUVmean in patients with ED (r~s~=0.81, p<0.001). SUVmax and SUVmean were not significantly associated with OS in patients with LD or ED or in the whole sample.

      Conclusion
      In patients with SCLC there was an association between higher SUVmax and higher TNM stage, as observed in patients with NSCLC. However, in this small patient cohort, we were unable to find evidence of an independent prognostic effect of SUVmax on overall survival.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-034 - Is loss of MGMT a therapeutic target in lung cancer? (ID 2118)

      09:30 - 09:30  |  Author(s): B. Solomon

      • Abstract

      Background
      MGMT is a DNA repair protein which removes alkylating DNA adducts from the O[6] position of guanine. Expression of MGMT is often silenced by promoter methylation in human cancers. MGMT methylation is a predictive marker for prolonged survival in glioblastoma patients treated with an alkylating agent, temozolomide. As MGMT methylation has been found in lung cancers, there is an increasing interest on the clinical utility of temozomolide in the treatment of human cancers. However, it is essential to use appropriate quantitative or semi-quantitative method methods to definitively establish the methylation status of the tumour.

      Methods
      We critically assessed MGMT methylation status in 6 lung cancer cell lines and 56 lung tumours using three different methodologies. We first assessed the MGMT methylation pattern using methylation sensitive – high resolution melting (MS-HRM). The methylation status at each CpG dinucleotide was assessed bisulfite pyrosequencing of methylated clones. The level of MGMT methylation was quantified using quantitative methylation specific PCR.

      Results
      MGMT methylation was found in 3 lung cancer cell lines by MS-HRM. The melting profiles of all methylated samples were indicative of heterogeneous methylation pattern by melting curve analysis. To examine the methylation status at each CpG sites of individual template, two MGMT methylated lung cell lines (H1666 and H69) were further tested by limiting dilution analysis and bisulfite pyrosequencing. The number and site of methylated CpG dinucleotides greatly varied in each template, confirming the heterogeneous methylation pattern in both cell lines. In 56 lung tumours, heterogeneous MGMT methylation was detected in seven samples (13%) by MS-HRM. The level of MGMT methylation was then estimated. 17 lung tumours, including the 7 MS-HRM positives and 10 additional tumours, were positive. However, the methylated level in all of the methylated samples was low, ranging from below 1% (12 samples) and up to 12%.

      Conclusion
      The level of MGMT promoter in lung cancer is difficult to estimate. Ideally clonal analysis should be used to estimate the proportion of methylated alleles. Alternatively, methylation profiling using MS-HRM followed by pyrosequencing can be used to identify tumours showing significant levels of methylation. If MGMT methylation is found only in a small proportion of tumour cells, it is unlikely to be a useful target for therapy. Overcalling of MGMT methylated tumours may provide the explanation for the lack of survival benefit with temozolomide treatment in MGMT-methylated lung cancer patients in a recent phase II clinical trial (NCT00423150). This indicates that incorporation of immunohistochemistry for the MGMT protein should also be part of the assessment of the MGMT status of lung cancer.