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S. Clarke



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

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO01.08 - Identifying Strategies For The Treatment Of Acquired EGFR Tyrosine Kinase Inhibitor Resistance (ID 3187)

      10:30 - 12:00  |  Author(s): S. Clarke

      • Abstract
      • Presentation
      • Slides

      Background
      The management of non-small cell lung cancer (NSCLC) is becoming increasingly personalised with the identification of oncogenic drivers of cancer cell growth which are able to be targeted therapeutically. The paradigm of advanced non-squamous NSCLC treatment now incorporates assessment of epidermal growth factor (EGFR) mutations and treatment with EGFR tyrosine kinase inhibitors (TKIs) in cases where sensitising mutations are found, which results in significant prolongation of progression-free survival compared to empirical chemotherapy. However, the emergence of acquired resistance to EGFR TKIs is almost universal and the two most common mechanisms of resistance include the acquisition of a second mutation in EGFR, the T790M mutation, and c-MET amplification. Approximately one-quarter of cases of resistance are yet to be defined mechanistically and furthermore, optimal subsequent treatment remains unknown. Further research is required to understand the molecular origins of the development of acquired resistance in order to develop rational treatment strategies that incorporate both targeted and cytotoxic therapies. This study is evaluating, using in vitro models, pathways involved in the development of acquired resistance to EGFR TKI and chemotherapy and evaluating critical differences according to EGFR mutation status.

      Methods
      A panel of human NSCLC cell lines with varying clinically relevant molecular characteristics is being assessed and used to develop resistance to various cytotoxic agents and EGFR TKIs, through chronic low dose exposure, as outlined in the table below:

      Cell Line Mutation Status EGFR TKI Sensitivity Resistant Cell Line Generated
      HCC827 EGFR Exon 19 deletion Sensitive Erlotinib; Cisplatin; Paclitaxel; Pemetrexed
      H1975 EGFR Exon 21 Point Mutation (L858R) and T790M mutation Resistant Cisplatin; Paclitaxel; Pemetrexed
      H1299 EGFR Wild-Type Resistant Cisplatin; Paclitaxel; Pemetrexed
      A549 EGFR Wild-Type and KRAS Mutation Resistant Cisplatin; Paclitaxel; Pemetrexed, HDAC-inhibitor
      Assessments of proliferation, cytotoxicity and key signalling pathways are being conducted to evaluate mechanisms of chemotherapeutic and targeted therapy resistance.

      Results
      Chronic low dose exposure has been successful in generating resistant cell lines to both chemotherapeutic agents and the EGFR TKI erlotinib. Cross-resistance to taxol in cisplatin-resistant cell lines has been observed, along with evidence of epithelial-to-mesenchymal transition in the development of EGFR TKI resistance. Antibody arrays of key signalling pathways are being conducted to confirm critical pathways of interest.

      Conclusion
      The panel of human NSCLC cell lines with parental lines harbouring various EGFR sensitising and resistance mutations and generated lines resistant to cytotoxic agents and EGFR TKI are a useful in vitro model to understand key pathways involved in the emergence of therapeutic resistance and to understand how both sensitising and resistant EGFR mutations influence response to cytotoxic agents. This will guide treatment strategies selected for evaluation in vivo that may influence future treatment selection for patients.

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    MO09 - Mesothelioma I (ID 120)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track:
    • Presentations: 1
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      MO09.07 - Disease and Patient Characteristics related to Survival in a large population-based cohort of patients with Malignant Pleural Mesothelioma (MPM) (ID 3184)

      16:15 - 17:45  |  Author(s): S. Clarke

      • Abstract
      • Presentation
      • Slides

      Background
      Despite advances in therapy, the prognosis of MPM remains poor (median overall survival (OS) of 9-12 months). Nevertheless, as described in surgical series, a small proportion of patients survive far longer. Previously identified prognostic factors in patients undergoing extra-pleural pneumonectomy (EPP) include histological subtype, gender and neutrophil-lymphocyte ratio (NLR). Similar factors including stage and performance status have also been shown to be prognostic in chemotherapy studies. We aim to assess in the general MPM patient population, what factors predict for better prognosis independent of the treatment path chosen.

      Methods
      We reviewed records of patients registered (2002 -2009) with the NSW Dust Diseases Board; a government compensation body for NSW workers with occupational asbestos exposure. We evaluated a priori prognostic factors including age, gender, histological subtype, staging on CT imaging and NLR using Kaplan Meier and Cox regression analysis, and by treatment interventions, smoking and asbestos exposure history. Exploratory subgroup analyses compared these factors in long-term (>20 months) survivors versus the remainder of the study population.

      Results
      We identified 913 patients: 90% male; median age 71.9 years; histological subtype (epithelioid 54%; biphasic 11%; sarcomatoid 16.3%; unknown 19%); stage on CT imaging (Tx-I-II 49%; III-IV 51%). 51% of patients received chemotherapy and 6% underwent EPP (of which 67% received chemotherapy. Median age of first occupational asbestos exposure was 18 years, cumulative duration of exposure, 24 years and latency from exposure to diagnosis, 50 years. Median OS was 10.0 months, 15.0 months (range(1-120) in patients receiving chemotherapy and/or EPP and 5.8 months (range 0-125) in patients receiving neither. On univariate analysis, younger age (<70 vs. >70yrs at diagnosis; 13.1 vs. 8.5 months; p<0.001); female gender (12.0 vs. 9.8months; p<0.001); epithelioid subtype (11.8 vs. 7.2 months ;p>0.001); and NLR <5 (12.9 vs. 7.5months; p<0.001) were associated with prolonged OS. Patients who underwent chemotherapy (13.6 vs. 7.2 months; p<0.001) and EPP (17.9 vs. 9.6 months; p<0.001) also had an improved survival. Smoking history (current/ex vs. never) and cumulative asbestos exposure did not affect survival. A trend to improved survival was noted with early stage disease (11.2 vs. 9.1 months; p=0.284) and younger age at first exposure (<18 vs. >18 years of age; 10.9 vs. 9.4 months; p=0.091). On multivariate analysis, age, gender, histological subtype, NLR, EPP and chemotherapy administration remained significant. 24% of patients demonstrated survival over 20 months. Of those, 14% underwent EPP, and 63% received chemotherapy. On multivariate analysis, epithelioid histology (p<0.001), chemotherapy use(p=0.002), undergoing EPP(p=0.01) and NLR<5(p=0.007) were independently associated with survival over 20 months.

      Conclusion
      In this large, population based cohort of MPM patients, we have validated age, gender, histological subtype and NLR as significant prognostic factors. Patients undergoing interventions such as EPP or chemotherapy demonstrated more favourable survival, however it is important to note that 86% of long survivors did not receive radical surgery, and 37% did not receive chemotherapy. As such, we hypothesise that apart from active treatment and inherent selection criteria, there are additional factors, such as favourable tumour biology, that seem to positively influence survival of MPM patients.

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    P1.14 - Poster Session 1 - Mesothelioma (ID 194)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P1.14-010 - Estimation of an optimal chemotherapy utilisation rate for malignant pleural mesothelioma: An evidence-based benchmark for patient care (ID 2535)

      09:30 - 16:30  |  Author(s): S. Clarke

      • Abstract

      Background
      Chemotherapy has been shown to provide a survival benefit in malignant pleural mesothelioma (MPM). There are wide ranging chemotherapy utilisation rates internationally (18 – 61%). This study aims to determine the optimal proportion of patients with MPM that should receive chemotherapy at least once during the course of their illness, based on the best available evidence, so that it can be determined whether chemotherapy is under-utilised in MPM.

      Methods
      An optimal chemotherapy utilisation tree was constructed using indications for chemotherapy identified from evidence-based treatment guidelines. Epidemiological data on the proportion of patient and tumour-related attributes for which chemotherapy was indicated (resectability of the tumour, degree of comorbidities and patient performance status) were obtained and merged with the treatment indications to calculate an optimal chemotherapy utilisation rate, using the decision analysis software (TreeAge Pro 2007). Sensitivity analyses were performed to assess the impact of major variations in the epidemiological data on the overall utilisation rate. This optimal rate was compared with reported actual rates of chemotherapy utilisation in the literature.

      Results
      Chemotherapy is recommended at least once in 65% of all MPM patients. Sensitivity analyses indicate an optimal utilisation rate ranging from 50 to 65% for at least once during the course of their illness. The optimal utilisation rate is consistently higher than the reported actual chemotherapy utilisation rates in United Kingdom (18%), Netherlands (36%), United States (37%), and Australia (54%).

      Conclusion
      An evidence-based model provided an optimal chemotherapy utilisation rate for patients with MPM of 65%. It can serve as a feasible measure of the quality of cancer care. Chemotherapy appears to be under-utilised in the management of MPM in a number of high-income countries.

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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-011 - Characterisation of chemo-resistant syngeneic orthotopic rat pre-clinical models of mesothelioma. (ID 1718)

      09:30 - 16:30  |  Author(s): S. Clarke

      • Abstract

      Background
      Malignant mesothelioma is an aggressive cancer with a low response to current therapies and consequently a poor prognosis. There is an urgent need to identify novel and more effective treatments to improve survival and quality of life for patients with mesothelioma. While a number of novel therapeutic agents have recently been examined in clinical trials, to date none of these has resulted in changes to standard management. This is due in part to a lack of robustness and relevance of the pre-clinical models used to assess new treatments. Therefore validated and biologically relevant pre-clinical models that demonstrate the clinical behaviour and drug sensitivity of mesothelioma, as well as typical resistance mechanisms, are necessary to improve the discovery of new treatments. Here we describe the generation and evaluation of chemotherapy resistant pre-clinical models of mesothelioma derived from the previously utilized syngeneic II-45 rat mesothelioma model.

      Methods
      Cell lines resistant to the current standard of care agents: cisplatin, pemetrexed gemcitabine, vinorelbine, and cisplatin and pemetrexed in combination, were generated by 15 rounds of exposure to the respective agent. Normal rat mesothelial cells (4/4 RM.4), the parental II-45 and the 5 resulting chemo-resistant mesothelioma cell lines were characterised for resistance to these and other agents. Tumours arising from syngeneic pleural engraftment of these cell lines were assessed by size, morphology, immunohistochemical markers of human malignancy, chromosomal changes and expression of genes involved in drug resistance and metabolism. Engrafted rats were assessed for survival, and circulating haematological, cytokine and biomarker profiles were generated and compared.

      Results
      Five different II-45 cell lines with approximately 2-fold resistance to the chemotherapeutic agent they were repeatedly exposed to, were established (cisplatin, p < 0.05; pemetrexed, gemcitabine, vinorelbine, p < 0.001). Cross resistance to other classes of anti-cancer agents also developed indicating potential multi-drug resistant phenotypes. Tumours derived from both the parental and chemo-resistant cell lines were immunohistochemically indistinct from human mesothelioma with positive labeling for WT1, calretinin, HBME-1, cytokeratin and popoplanin and negative labeling for two carcinoma related markers TTF-1 and CD15. Homozygous deletion of p16[INK4A]/p14[ARF], and increased expression of several members of the ATP-binding cassette transporter superfamily and Androgen receptor (AR) were demonstrated, consistent with findings in human mesothelioma. Corresponding with biomarkers studies in human disease, increased levels of osteopontin (p < 0.01), mesothelin (p < 0.01), vascular endothelial growth factor (p < 0.001) and neutrophil to lymphocyte ratio were identified relative to control bloods. Further, the acquisition of chemo-resistance resulted in changes to tumour morphology with tumours ranging from essentially epithelioid in the gemcitabine resistant tumours to entirely sarcomatoid in the combination (cisplatin and pemetrexed) resistant tumours. Overall survival was also affected by the acquisition of resistance with rats with pemetrexed resistant tumours having decreased survival.

      Conclusion
      These models display many features corresponding with the human disease, and thus provide powerful and robust pre-clinical platforms for in vivo mesothelioma studies.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-015 - Novel plasma proteins associated with prognosis in malignant pleural mesothelioma (ID 1337)

      09:30 - 16:30  |  Author(s): S. Clarke

      • Abstract

      Background
      The search for novel biomarkers to define more successful and individual treatment approaches represent an important challenge for those involved in the care for patients with malignant pleural mesothelioma (MPM). In this exploratory study, we have systematically investigated the proteins present in plasma of MPM patients and correlated their levels with disease outcomes.

      Methods
      Plasma samples from twelve MPM patients (6 ‘short-’ and 6 ‘long-term’ survivors from parallel phase II studies investigating thalidomide) were used for proteomic analyses. Our series included samples from 9 patients with epithelial MPM and 3 patients with biphasic MPM. Plasma samples were immuno-depleted of the 14 most abundant proteins prior to labelling for isobaric tag for relative and absolute quantitation (iTRAQ) analysis using mass spectrometry. The most promising candidates and mesothelin were chosen for selected reaction monitoring mass spectroscopy (SRM-MS) quantification and enzyme-linked immunosorbent assay (ELISA) validation. Statistical analyses using T-Test of peak areas were used to identify proteins that were differentially expressed between the short- and long-term survivor groups.

      Results
      Median survival of short- and long-term survivors (1.2 and 38.3 months, respectively) differed significantly (p = 0.001). This was also the case for the neutrophil-to-lymphocyte ratio (NLR) that was significantly higher in the group of short-term survivors (p=0.03). Other baseline characteristics did not reveal major differences between the short- and long-term survivors. The total number of proteins identified was 226 (1% false discovery rate) in iTRAQ. A number of those were found to be differentially expressed between short- and long-term survivors (≥1.2-fold change; p≤0.05) by iTRAQ: selenoprotein P; tetranectin; insulin-like growth factor-binding protein 2 (IBP2); osteonectin (SPARC); platelet basic protein (CXCL7); and attractin. Mesothelin was assessed to validate the proteomic methodology: SRM-MS quantification was highly correlated with the MESOMARK ELISA values with a Pearson correlation of 0.82 (p=0.001). SRM-MS quantification revealed that the concentrations of attractin (p=0.02), tetranectin (p=0.003) and selenoprotein P (p=0.001) were higher in long-term survivors. In contrast, there was a trend for an increase in the concentration of SPARC (p=0.32), IBP2 (p=0.12) and CXCL7 (p=0.19) to be correlated with shorter survival. Furthermore, quantification by ELISA demonstrated an association between long survival and low concentration of SPARC (p=0.07) as well as high tetranectin (p=0.13).

      Conclusion
      We have demonstrated the feasibility of using the iTRAQ and SRM-MS proteomic techniques to investigate potential prognostic protein markers in plasma of MPM patients. Potential prognostic biomarkers worthy of further studies include SPARC and tetranectin and we plan to validate these in a larger clinical cohort.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-030 - Eastern Cooperative Oncology Group (ECOG) score: Agreement between non-small-cell lung cancer (NSCLC) patients and their oncologists and clinical implications (ID 1792)

      09:30 - 16:30  |  Author(s): S. Clarke

      • Abstract

      Background
      Oncologists use ECOG score to assess patients’ performance status (PS) and guide treatment decisions, but patients and doctors do not necessarily agree on their score. We compared ECOG scores assessed by NSCLC patients and their oncologists to determine if this has implications on treatment and survival prediction.

      Methods
      NSCLC patients who underwent chemotherapy in prospective inter-ethnic difference and nutrition studies at Concord Hospital were included. Patients self-assessed their ECOG score as part of the Patient-Generated Subjective Global Assessment questionnaire prior to chemotherapy. Kappa was used to assess agreement of ECOG score between patients and oncologists. Survival was calculated from date of chemotherapy, using Kaplan Meier method.

      Results
      79 patients (median age 63 years, 86% Stages IIIB/IV, median survival of 15.5 months) were included. ECOG scores differed in 34 (43%) cases (Table).The interrater reliability between patients and their oncologists was Kappa = 0.35 (p <0.001). Figure 1 If patient ECOG scores were used, 11 patients (14%) would be deemed unfit for chemotherapy (ECOG≥3) and 21 patients (27%) would be excluded from clinical trials (ECOG≥2). ECOG status (0 versus >0) irrespective of assessor was predictive of overall survival (18.7 vs. 12.1 months with p=0.023 and 17.4 vs. 11.1 months with p=0.017 for patient and oncologist-assessed ECOG respectively). In patients whose ECOG score was assessed to be 0 by their oncologist (n=39), a worse survival was associated with a poorer patient assessed PS (median survival 16.7 vs. 18.2 months for patient assessed ECOG >0 vs. ECOG=0 respectively; p=0.31).

      Conclusion
      Both physician and patient-assessed ECOG scores are predictive of overall survival. In this study, there was only fair agreement in ECOG assessed by NSCLC patients and their oncologists, with patient scores usually poorer. A number of patients would have excluded themselves from therapeutic interventions including clinical trials based on their ECOG PS rating. Patient-assessed ECOG scores of > 0 may be associated with worse survival despite their oncologist’s more optimistic scoring, a finding which may be incorporated to benefit clinical decision-making.

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    P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.02-003 - ATP7A is a novel determinant of toxicity and response in advanced non-small cell lung cancer patients receiving paclitaxel and carboplatin (ID 700)

      09:30 - 16:30  |  Author(s): S. Clarke

      • Abstract

      Background
      Genetic variability can influence the pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC). Additionally, the prevalence of genetic variations often differs between ethnic groups and may account for observed interethnic variability in drug efficacy. We aimed to undertake a pharmacogenomic investigation to account for patient variability in order to improve dosing and patient selection in NSCLC.

      Methods
      76 advanced NSCLC patients from Caucasian (n = 50) and Asian (n = 26) ethnicity were prospectively recruited into the study at Concord Repatriation General Hospital from 2007-2011. All patients received paclitaxel (175mg/m[2]) and carboplatin (target AUC 6 mg/mL•min) for an intended 6 cycles. A candidate gene approach was used to select single nucleotide polymorphisms (SNPs) for pharmacogenomic analysis. HPLC with population pharmacokinetic modelling (NONMEM) was used to obtain pharmacokinetic data (n = 61). Toxicities were assessed according to CTCAE v 4.0 and response was measured by CT scans according to RECIST criteria. Blood DNA was genotyped by the Australian Genetics Research Facility using a MassARRAY® iPLEX Gold system on a Sequenom mass spectrometer. SNPs were assessed for linkage disequilibrium, Hardy-Weinberg equilibrium and interethnic differences in allele frequency. Regression analysis was undertaken to associate SNPs with drug pharmacokinetics, toxicities and response.

      Results
      42 SNPs from 21 genes were selected and genotyped in patients. Regression analysis identified 12 SNPs significantly associated to paclitaxel pharmacokinetics, patient toxicities and response. SNPs rs2306283 and rs11615, in SLCO1B1 and ERCC1 respectively, associated with paclitaxel clearance. Previously published SNPs in CYP2C8, CYP1B1, ABCB1, ABCC10, SLCO2B1, GSTP1, ATP7A, ERCC1 and CCND1 were found to be associated with patient toxicities. Three SNPs, rs2306283, rs1056836 and rs2306168, encoded by SLCOB1, CYP1B1 and SLCO2B1 respectively, had interethnic difference in SNP prevalence and associated to patient outcomes. SNP rs2227291 in ATP7A associated with patient response and to nausea and anaemia.

      Conclusion
      The study associated various SNPs to drug pharmacokinetics, patient toxicities and response which could be integrated into future personalisation efforts of paclitaxel and carboplatin. Furthermore, SNPs with interethnic differences may provide clues to understand interethnic variability in drug efficacy. Finally, a novel SNP identified in ATP7A associated with patient response and toxicity. The ATP7A gene encodes a protein that has been linked to resistance to platinum based drugs, however, the SNP has unknown functional effects which require further elucidation.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-046 - ROS1 overexpression by immunohistochemistry in non-small cell lung cancer: clinical characteristics, natural history and potential new therapeutic target based on two Australian cases (ID 3081)

      09:30 - 16:30  |  Author(s): S. Clarke

      • Abstract

      Background
      Recent years have seen worldwide interest in the study of driver mutations in lung cancer, in particular epidermal growth factor receptor mutation (EGFR) and anaplastic lymphoma kinase gene rearrangement (ALK). ROS1 gene rearrangement is a recently identified driver mutation and potential therapeutic target for crizotinib and similar agents. However little is known of the natural history of patients with ROS1, and moreover the diagnostic value of immunohistochemistry (IHC) compared to fluorescent in-situ hybridization (FISH).

      Methods
      12 patients from a single Australian tertiary institution with advanced non-small cell lung cancer (NSCLC) were screened for ROS1 overexpression and gene rearrangement. Selection was based on negative testing for EGFR and ALK, and unusually long natural history.

      Results
      We report 2 patients with ROS1 overexpressed advanced NSCLC, their unique characteristics, long natural history and the use of IHC as a complementary method to FISH in identifying these patients. Mr GL was a 62 year-old Caucasian man and lifelong non-smoker who presented with an incidental 19mm subpleural left lower lobe lung nodule found on computed tomography (CT) when he was treated for pneumonia in 2008. He was monitored with CT for his pulmonary nodule and pre-existing interstitial lung disease. In 2011, CT and subsequent positron emission tomography (PET) showed new regional lymphadenopathy and widespread sclerotic bone disease with the pulmonary nodule unchanged in size but moderately glucose avid. Axillary and supraclavicular lymph node biopsies confirmed metastatic adenocarcinoma consistent with a lung primary. EGFR and ALK testing was negative. He received induction and maintenance chemotherapy until disease progression in 2013. His original biopsy tested negative for ROS1 rearrangement by FISH but stained strongly positive for ROS1 overexpression by IHC using the Epitomics rabbit monoclonal antibody (D4D6) with diffuse cytoplasmic positivity. He was commenced on crizotinib, achieving and maintaining stable disease after three months. Mrs MM was a 54 year-old Caucasian woman and lifelong non-smoker who presented with an incidental 26mm right lower lobe lung nodule found on CT when she presented with left sided chest pain in 2009. PET and endobronchial biopsy of mediastinal lymph nodes confirmed stage IIIA lung adenocarcinoma. EGFR and ALK testing was negative. She received neo-adjuvant chemotherapy, followed by right lower lobectomy and post-operative radiotherapy. In 2010 she developed right supraclavicular lymph node recurrence and achieved radiological complete response after radiotherapy. In 2011 she developed another isolated nodal recurrence in the right supraclavicular fossa, which was surgically resected and confirmed adenocarcinoma. It stained strongly positive for ROS1 overexpression by IHC and positive for ROS1 rearrangement by FISH. In 2013, PET found an isolated hepatic metastasis. She was commenced on crizotinib with plans for re-staging and consideration for liver directed therapy. Clinical progress of the patients will be updated and presented.

      Conclusion
      Our cases of ROS1 overexpressed NSCLC illustrate unique patient characteristics of never-smoking status, adenocarcinoma histology, negative testing for EGFR and ALK, and an unusually long natural history. Our cases highlight the need for greater understanding of the predictive value of ROS1 overexpression by IHC as opposed to FISH alone for targeted therapy.