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C.I. Selinger



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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 2
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      P3.06-017 - Distinctive Insulin-Like Growth Factor 1 gene copy number and protein expression in non-small cell lung cancer (ID 1753)

      09:30 - 09:30  |  Author(s): C.I. Selinger

      • Abstract

      Background
      The insulin-like growth factor (IGF) pathway is involved in the development and progression of many tumours and there is growing preclinical evidence that blockade of this pathway has anti-tumour effects in NSCLC. IGF receptors (IGFR) are another potential target for targeted treatment of NSCLC and a number of agents are already undergoing clinical trial. Biomarkers are needed to select patients most likely to derive clinical benefit from these agents. The downstream pathway components of IGF1R and MET activation include PI3K and AKT, which are other potential biomarkers currently being investigated in this patient cohort. IGF1R has also been implicated in acquired resistance to EGFR-TKI treatments. Only a few small retrospective studies have investigated the prognostic role of IGF1R in NSCLC and the relationship with EGFR mutations is not known.

      Methods
      IGF1R status was evaluated by chromogenic silver in situ hybridization (ISH) and immunohistochemistry (IHC) in tissue microarray sections from a retrospective cohort of 264 surgically resected NSCLCs and results were compared to clinicopathological features and patient survival. Patients were classified as IGF1R gene amplification (either presence of tight gene clusters, IGF1R to CEN15 ratio ≥ 2, or ≥ 15 copies of IGF1R per cell in ≥ 10% of analysed cells); high polysomy (≥ 4 copies of IGF1R in ≥ 40% of tumour cells); low copy number (< 4 copies of IGF1R in < 40% of cells). Patients were also grouped as IGF1R-positve (amplification or high polysomy) or IGF1R-negative (low copy number).

      Results
      High IGF1R gene copy number was identified in 77 cases (29.2%) in which there were 32 amplified IGF1R cases (12.1%) and 45 high-polysomy IGF1R cases (17%). Increased copy number of IGF1R was more common in squamous cell carcinomas (SCC) compared to large cell carcinomas (LCC) or adenocarcinomas (ADC) (p<0.05). There was no correlation between IGF1R gene copy number status and other clinicopathological features including patient age, gender, smoking status, tumour size, vessel, perineural or lymphatic invasion, grade or stage. IGF1R copy number alteration in primary tumours was highly correlated with IGF1R copy number status in metastatic tumours (p<0.01). High IGF1R protein expression was observed in 61/259 (23.6%) primary tumours and 14/215 (6.5%) normal adjacent bronchial mucosae. High expression of IGF1R protein was significantly associated with SCC in comparison with non-SCC primary tumours, as well as with lymphatic and vessel invasion. There was a moderate correlation between IGF1R copy number status (positive versus negative) and IGF1R protein expression (high versus low) (Cramer’s V=0.3, p-value <0.001). Both IGF1R copy number status and protein expression were not associated with patient overall survival in univariate analyses (p>0.05).

      Conclusion
      High IGF1R gene copy number and its protein expression are frequent in NSCLC, particularly in SCC. However, alterations of IGF1R are not associated with patient prognosis. IGF1R gene copy number can readily be assessed in formalin fixed paraffin embedded tissue and warrants further investigation as a potential biomarker of targeted therapy in NSCLC.

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      P3.06-032 - Evaluation of Anaplastic lymphoma kinase (ALK) rearrangements using ALK/EML4 TriCheck Fluorescence In Situ Hybridisation (FISH) in Non-Small Cell Lung Cancers (NSCLC) and its utility for equivocal cases. (ID 2487)

      09:30 - 09:30  |  Author(s): C.I. Selinger

      • Abstract

      Background
      Accurate assessment of ALK gene rearrangement in NSCLCs is critical to identify patients likely to respond to crizotinib. Currently, the gold standard for identifying ALK gene rearrangements is FISH and the Abbott Molecular ALK break apart probe is commonly used. We evaluated a new ALK/EML4 TriCheck FISH Probe for the detection of ALK rearrangements and confirmation of EML4 as the inversion partner. In addition, we evaluated its use as an ancillary FISH probe for use in cases with subtle, equivocal or atypical ALK FISH patterns.

      Methods
      ALK FISH was prospectively performed on 29 routine diagnostic cases using the ALK/EML4 TriCheck Probe (ZytoVision) and the Vysis ALK Break Apart FISH Probe (Abbott Molecular). ALK immunohistochemistry (IHC) was performed using the 5A4 clone antibody (Novocastra) and D5F3 clone antibody (Cell Signaling Technology).

      Results
      Both probes were concordant in all cases, except for one case which showed an atypical signal pattern using the Abbott Molecular ALK probe. This case was technically negative using standard scoring criteria for the Abbott probe, despite positive ALK IHC, but was confirmed as positive using the ZytoVision TriCheck probe. Two additional cases which were equivocal (10-16% ALK rearrangement), were confirmed to be positive for ALK rearrangement using the ALK/EML4 TriCheck probe. Of the 10 ALK rearranged cases, 4 showed evidence of EML4 translocation.

      Conclusion
      The ALK/EML4 TriCheck FISH Probe is useful for the detection of ALK gene rearrangements, including those involving EML4 as the translocation partner, especially for borderline cases or cases displaying atypical signal patterns, where an additional unique ALK FISH probe can provide further confirmation of rearrangement.

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    P3.18 - Poster Session 3 - Pathology (ID 177)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P3.18-003 - ROS1 Gene Rearrangements in Non-Small Cell Lung Carcinoma - A New Genetic Target that can be Identified by Immunohistochemistry and FISH (ID 1482)

      09:30 - 09:30  |  Author(s): C.I. Selinger

      • Abstract

      Background
      Targeted therapies aimed at specific molecular genetic alterations are revolutionizing cancer treatment, particularly in non-small cell lung cancer (NSCLC). ROS1 is an oncogene that encodes a transmembrane tyrosine kinase receptor that has high homology with the intracellular kinase domain of ALK. Driver mutations involving translocation of the ROS1 gene have recently been identified in NSCLC and show promise as a target for tyrosine kinase inhibitors. In this study we aimed to: (1) Investigate the incidence and clinicopathological features of NSCLCs harbouring ROS1 rearrangements in an Australian population. (2) Investigate the accuracy of immunohistochemistry (IHC) compared to FISH at identifying tumours with ROS1 rearrangements.

      Methods
      We tested for ROS1 translocations using both a FISH breakapart probe (Zytovision and Abbott Molecular) (≥15% cells with split signals or single green 3' signal considered positive for rearrangement), and immunohistochemistry (D4D6 clone, Cell Signaling Technology). Testing was undertaken on both (1) A retrospective cohort of 316 early stage lung adenocarcinomas in tissue microarrays. (2) A prospective cohort of 42 NSCLC, selected on clinical grounds for mutation testing (eg EGFR/KRAS/ALK negative samples and young age or never/light smoker).

      Results
      In the retrospective cohort, only 1 case was positive for ROS1 gene rearrangement by FISH (0.3% incidence). ROS1 IHC identified positive staining in 7 (2.0%) cases, including the FISH+ case. ROS1 IHC had a sensitivity of 100% and specificity of 98% for identifying ROS1 gene rearrangements. In the prospective cohort of 42 cases, 4 cases with ROS1 gene rearrangement were identified by FISH and all 4 cases showed positive ROS1 immunohistochemical staining. Of the total 5 cases with ROS1 gene rearrangement, all occurred in adenocarcinomas from female patients with an age range of 33-81 years (mean 58). Four of the five patients were non-smokers and two were of Asian ethnicity. All 5 cases were negative for ALK rearrangements and in the 4 cases where EGFR status was known, they were all wild type.

      Conclusion
      ROS1 gene rearrangements occur in a very small percentage of lung adenocarcinomas with distinctive clinicopathological features and appear to be mutually exclusive with other driver mutations in the small number of positive cases available for evaluation. Screening with IHC may be a suitable method of reducing the number of cases requiring FISH testing.