Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

R. Soo



Author of

  • +

    MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • +

      MO01.01 - Next generation sequencing of circulating tumour cells captured by antibody-independent enrichment and matched primary tumours/metastases in patients with non-small cell lung cancer (ID 3311)

      10:30 - 10:35  |  Author(s): R. Soo

      • Abstract
      • Slides

      Background
      Circulating tumour cells (CTCs) are considered the seeds of metastasis, and characterization of CTCs promises novel insights into metastasis, new targets for intervention, and less-invasive samples for assessing tumour status. CTCs however are rare in circulation and thus highly sensitive tools are required for their reliable capture and analysis. Antibody-based platforms using candidate gene-based approaches have begun to provide insights into CTCs. However tumour heterogeneity and the dependence of these methods on antigen expression has made antibody-independent methods of interest. The Clearbridge ClearCell System is a microfluidic-based platform that enables antibody-independent capture and retrieval of CTCs based on differences in the biomechanical characteristics of blood cells and CTCs. Next Generation Sequencing (NGS) has emerged as a tool to perform massive parallel sequencing of genomic regions with high efficiency and accuracy. The aim of this study was to perform NGS analysis of CTCs captured by antibody-independent methods, and their matched primary tumour or metastases samples, in patients with NSCLC.

      Methods
      Three matched CTC and primary tumour samples and three matched CTC and metastases samples were obtained from patients with NSCLC. Whole blood samples were also obtained from the patients for germline DNA. Five patients had adenocarcinoma and none of the patients had received targeted therapy prior to biospy of the metastatic lesions. CTCs were captured and retrieved from 2ml whole blood using the Clearbridge ClearCell System near the time of tumour sampling. DNA was extracted from CTCs, tumour tissue, and whole blood using the Qiagen QiaAMP DNA Micro Kit, DNAeasy Blood and Tissue kit , and Biorobot EZ1 workstation respectively. NGS was performed on the Ion Torrent PGM Sequencer using the AmpliSeq Comprehensive Cancer Panel targeted to 409 genes prominent in cancer. DNA variants were identified using Ion Torrent Software Suite v3.4, and pathway analysis was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID).

      Results
      After subtraction of DNA variants found in whole blood, the average number of variants in CTC, primary tumour and metastases samples was 283 (range: 110-470), 433 (70-1002), and 242 (81-166) respectively. The concordance in variants between CTC and primary tumour samples was 22% (15-29%) and between CTC and metastases samples was 29% (20-38%). Genes frequently mutated in matched CTCs and primary tumours/metastases included NOTCH2, AKT1, and RET. Pathway analysis of genes with DNA variants revealed an enrichment of genes involved in mTOR signalling in both CTC/primary and CTC/metastases samples. In CTC/metastases samples, pathways including the JAK-STAT and B-cell receptor pathways were additionally enriched.

      Conclusion
      Our results have highlighted a high level of genetic variability between CTCs and their matched tumours, reflective of high tumour heterogeneity. Preliminary analysis has identified genes and pathways with alterations in CTCs that could be potential targets for systemic treatment.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MO16 - Prognostic and Predictive Biomarkers IV (ID 97)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      MO16.06 - Clinical, structural and biochemical characterization of EGFR exon 20 insertion mutations in lung cancer (ID 745)

      16:50 - 16:55  |  Author(s): R. Soo

      • Abstract
      • Presentation
      • Slides

      Background
      Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for ~10% of EGFR-mutated non-small-cell lung cancer (NSCLC), for the most part occur at the N-lobe of EGFR after its C-helix (after amino-acid M766) and have unsolved patterns of response to ATP-mimetic EGFR tyrosine kinase inhibitors (TKIs).

      Methods
      To understand the patterns of resistance or response to EGFR TKIs of EGFR exon 20 insertion mutations, we decided to study representative mutations using in vitro systems, structural models and also NSCLCs with these specific EGFR mutations.

      Results
      We selected three mutations located within the C-helix (A763_Y764insFQEA [identical to D761_E762insEAFQ], Y764_V765insHH and M766_A767insAI) and four mutations following the C-helix (A767_V769dupASV [identical to V769_D770insASV], D770_N771insNPG, D770_N771insSVD [identical to S768_D770dupSVD] and H773_V774insH [identical to P772_H773insH]) mutations. Our data indicates almost all EGFR exon 20 insertions are resistant to submicromolar concentrations of gefitinib or erlotinib; data that mirrors the lack of clinical response of NSCLCs with these mutations. The crystal structural and enzyme kinetic studies of a prototypical post C-helix EGFR TKI-resistant insertion, between residues D770_N771 (D770_N771insNPG), highlight that these mutations favor the active conformation (i.e., are activating), don’t alter EGFR’s ATP-binding pocket and are less sensitive than TKI-sensitive mutations. D770_N771insNPG is predicted to be 7.66 fold less sensitive than the TKI-sensitive EGFR-L858R. Unexpectedly, we identified the atypical EGFR-A763_Y764insFQEA as the only EGFR exon 20 insertion hypersensitive to EGFR TKIs using enzyme kinetic and cell line models. In patients with EGFR exon 20 mutated NSCLCs, the response rates to gefitinib or erlotinib were significantly higher for A763_Y764insFQEA (2/3; 66.6%) when compared to all other mutations within or following the C-helix (0/17, 0%; p=0.0158). The unorthodox homology model of A763_Y764insFQEA suggests a mechanism of activation (by shifting the register of the C-helix N-terminal) related to TKI-sensitive mutations (such as L858R or L861Q).

      Conclusion
      Our findings not only explain the intricate interplay between different EGFR mutations and their response to EGFR TKIs, but also have clinical implications for the treatment of EGFR exon 20 insertion mutated NSCLCs. Therefore, based on our data and previously published reports the aforementioned mutations affecting amino acids V765 to V774 should be classified as non-sensitizing to the reversible EGFR TKIs gefitinib and erlotinib. Our models may usher the development of EGFR TKIs specific for EGFR exon 20 insertion mutations.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    O18 - Cancer Control and Epidemiology II (ID 133)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
    • +

      O18.02 - Impacts of environmental tobacco smoke on EGFR mutations and ALK rearrangements in never smokers with non-small cell lung cancer: Analyses on a prospective multinational ETS registry (ID 1255)

      10:40 - 10:50  |  Author(s): R. Soo

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR and ALK are important driver mutations in never smokers. While we reported the significant association of increased environmental tobacco smoke (ETS) with EGFR mutations in Japanese cohort (Kawaguchi, Clin Cancer Res, 2011), it has not been fully understood in other ethnicities and also the correlation of ETS with ALK has not been reported yet. In this study, we evaluated the association of ETS with the prevalence of EGFR mutations and ALK translocations in various ethnicities including East-Asia (Japan, Korea, China, and Singapore) and the USA.

      Methods
      ETS exposure on never smokers with non-small cell lung cancer (NSCLC) was evaluated using the standardized questionnaire including exposure period, place, and duration. Cumulative dose of ETS (CETS) was defined as a sum of the number of the exposure years in childhood/ adulthood and at home/ workplace, and was treated as a continuous variable or quintile. EGFR mutations and ALK rearrangements were tested by PCR-based detection and fluorescence in situ hybridization, respectively. Multivariate analyses were done using the generalized linear mixed model (GLIMMIX procedure, SAS v9.3).

      Results
      From March 2008 to December 2012, 498 never smokers with NSCLC were registered with the following patient characteristics: ethnicity (nationality) of Asian/ Caucasian/ others, 425 (Japanese 250, Korean 102, Chinese 46, others 2)/ 48/ 25; male/ female, 114/ 384; age <65/ >=65, 286/ 212; histology of adenocarcinoma/ BAC/ squamous cell carcinoma/ adenosquamous cell carcinoma/ other NSCLC, 459/ 12/ 13/ 5/ 9; frequency (%) of CETS < median CETS (40 years) in Japanese/ Korean/ Chinese/ Caucasian, 32.8/ 44.1/ 71.7/ 83.3. EGFR status was wild type 43.6%, exon 19 deletion 25.3%, L858R 21.5% and other mutations 9.6%. ALK status was wild type 52.0%, rearranged 10.6% and unknown 37.3%. Average CETS (years) of NS with EGFR (+), ALK (+) and wild type tumors were 45.4, 26.9 and 37.7, respectively. In multivariate generalized linear mixed model, incidence of activating EGFR mutations, not ALK rearrangements, was significantly associated with the increment of CETS in female, not in male gender. Odds ratios (OR) for EGFR mutations in female (n=384) were 1.084 (95% CI, 1.003-1.171; p=0.0422) for each increment of 10 years in CETS while OR in male (n=114) were not significant (OR 0.890; 95% CI, 0.725-1.093; p=0.2627). OR for ALK rearrangements in female (n=238) and those in male gender (n=74) were 0.930 (0.791-1.094; p=0.3814) and 0.854 (0.620-1.178; p=0.3319).

      Conclusion
      Increased ETS exposure was closely associated with EGFR mutations in never smokers with female gender and NSCLC in the expanded multinational cohort. However, the association of ETS and ALK rearrangements in never smokers with NSCLC was not significant.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      P1.11-037 - Phase II activity of the HSP90 inhibitor AUY922 in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) (ID 2730)

      09:30 - 09:30  |  Author(s): R. Soo

      • Abstract

      Background
      AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. HSP90 is a molecular chaperone of oncogenic client proteins relevant in NSCLC pathogenesis, including epidermal growth factor receptor (EGFR), which is mutated in 10% of NSCLC cases in the Western population, and in 30% of NSCLC cases in the Asian population. We report here a subgroup analysis of data from the 2 EGFR mutation strata of a Phase II study of AUY922 in patients with previously treated, advanced NSCLC stratified by molecular status.

      Methods
      Patients with advanced NSCLC who progressed following ≥1 prior line of therapy, received AUY922 (70 mg/m[2]) as a once-weekly, 1-hour infusion. Patients with EGFR-mutant NSCLC were divided into 2 strata: pretreated EGFR-mutant (>2 prior regimens), or less-heavily treated EGFR-mutant (≤2 prior regimens and documented response to an EGFR tyrosine kinase inhibitor [TKI]). The primary endpoint was confirmed response, stable disease at 18 weeks, or no clinical benefit. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety/tolerability.

      Results
      At the cut-off date of 14 March 2013, 66 patients with EGFR-mutant NSCLC had been treated (median age 58 years; 67% female; 94% adenocarcinoma; EGFR-initial stratum n=35; less-heavily pretreated EGFR-mutant stratum n=31); all patients had been pretreated with an EGFR TKI. Clinical activity of AUY922 was seen, with any responses (investigator assessed), in 12/66 (18.2%) patients. A total of 34/66 (51.5%) patients had a best overall response of stable disease or non-confirmed partial response; of these patients, 11 (32%) had stable disease for ≥18 weeks. The 18-week PFS rate was 39% in all patients with ≤2 prior lines of therapy (n=43), and 28% in all patients (n=21) who had received >2 lines of therapy. The most frequent adverse events (AEs; any grade, regardless of study drug relationship) were diarrhea (73%), nausea (47%), decreased appetite (38%), fatigue (35%), and headache and night blindness (both 29%). Most AEs were Grade 1 or 2; Grade 3 or 4 AEs included diarrhea (9%), and fatigue, decreased appetite, and hyponatremia (all 6%).

      Conclusion
      AUY922 had an acceptable safety profile. Strong evidence of clinical activity was demonstrated in EGFR TKI-pretreated patients with EGFR-mutant NSCLC. Median PFS, OS and biomarker data for the EGFR-mutant stratum will be presented.