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R. Lake



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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO19.03 - The effects of epidermal growth factor (EGFR) receptor inhibitors on the immune system in patients with advanced non-small cell lung cancer (NSCLC) (ID 3152)

      10:30 - 12:00  |  Author(s): R. Lake

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR tyrosine kinase inhibitors (TKIs) have an important role in the treatment of NSCLC, particularly in the context of activating mutations, but resistance invariably develops. Recently, the immune checkpoint blockers anti-PD1 and anti-PDL1 were the first immunotherapies to demonstrate activity in advanced lung cancer. As immunotherapies such as anti-CTLA4, anti-PD1 and anti-PD-L1 antibodies enter clinical practice, there is potential to combine immunotherapies with TKIs to improve patient outcomes. The immune effects of EGFR-TKIs have not been elucidated, and the aim of this study is to examine the effect of TKIs on the immune response in patients with NSCLC, to provide a rationale and pilot data to underpin future clinical development of combinations of TKIs and immunotherapy.

      Methods
      Patients with advanced NSCLC who were commencing an EGFR-TKI were included in this prospective study. Eligible patients had a confirmed diagnosis of NSCLC, were treated with a single-agent EGFR-TKI , had no concurrent autoimmune disease and received no chemotherapy within 21 days, or corticosteroid therapy within 3 days of study entry. Peripheral blood samples were collected before commencing a TKI and 7 days, 21 days and 8 weeks after start of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and immediately frozen for subsequent analysis by 8-colour flow cytometry for relevant surface and intracellular marker expression. 4 panels were developed to examine the activation and proliferation status of effector CD8[+] T and CD4[+] T-regulatory cells (Tregs), enumeration of dendritic cells and B-cells, as well as the inhibitory pathway programmed death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 on T cells and antigen-presenting cells. Changes in immune parameters will be correlated with overall survival (OS) and radiological response (RECIST 1.1 criteria) at 8 weeks post-treatment.

      Results
      33 eligible patients were prospectively enrolled. Histopathology was adenocarcinoma (n=23), squamous cell carcinoma (n=7) and NSCLC not otherwise specified (NOS, n=3)). 12 patients had an activating EGFR mutation, 11 were EGFR wild type, and mutation-status was unknown in 10. 6 patients received the TKI gefitinib and 4 received erlotinib as first-line treatment for EGFR-mutation positive disease. 22 patients received erlotinib and 1 patient received afatinib as second or subsequent line therapy. At time of this report, 22/33 patients were deceased. Median OS from study entry was: all patients (7.7 months); mutation-positive (11.1 months); and mutation negative (4.4 months). Samples for 13 patients (2 were mutation-positive) have been analysed for effector T cell and Treg panels and no significant changes were seen between baseline and subsequent time points. Data will be presented for all samples.

      Conclusion
      This is the first study to explore to the immune effects of EGFR-TKIs. Initial results have not revealed a significant effect on peripheral T-cells, and analysis of remaining patient samples and other panels is in progress. An understanding of the immune effects of targeted therapies will be crucial in the rational development of strategies for incorporating immunotherapy into the anti-EGFR treatment paradigm, in an era of promising immunotherapy and checkpoint blockade approaches.

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    MS24 - Mesothelioma Biology and Biomarkers (ID 41)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Mesothelioma
    • Presentations: 1
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      MS24.1 - A Tractable Animal Model of Mesothelioma (ID 574)

      14:00 - 15:30  |  Author(s): R. Lake

      • Abstract
      • Presentation
      • Slides

      Abstract
      We have developed a novel transgenic mouse (MexTAg) where cellular transformation is driven by the SV40 (simian virus 40) large T antigen (TAg). In these mice, TAg is specifically targeted to the mesothelial compartment because it is expressed under the control of a tissue specific promoter. MexTAg mice uniformly develop mesothelioma after exposure to asbestos, with no spontaneous formation of other tumours. The key differences between MexTAg and wild type animals are the higher incidence and the shorter latency of the disease. Survival after diagnosis is not different suggesting that TAg does not drive a more aggressive disease. The model is comparable to human mesothelioma because of the eliciting carcinogen and because the location, pathology, molecular lesions and tumour response to therapy are similar (Robinson et al., 2006; Robinson et al., 2011). It is thought that asbestos fibres drive cellular transformation via the production of reactive oxygen species and the induction of chronic local inflammation. Accordingly, we have begun to test antioxidants and anti-inflammatory drugs as potential cancer prevention agents. We have reported that dietary supplementation with the antioxidants, vitamins A, E and selenium does not affect overall survival nor the time to progression of asbestos-induced mesothelioma in MexTAg mice (Robinson et al., 2012). We have extended our analysis to vitamin D and compared survival of asbestos-exposed MexTAg mice provided with diets supplemented (4500 IU/kg feed) or deficient in vitamin D (cholecalciferol). Survival of supplemented mice was significantly shorter than mice given standard diet (median survival, 29 and 32.5 weeks respectively). Mice deficient in vitamin D developed mesothelioma at the same rate as control mice. We conclude that vitamin D is unlikely to moderate the incidence of disease in asbestos exposed populations or to ameliorate the pathology in patients with established mesothelioma. Mesotheliomas in MexTAg mice respond to cytotoxic chemotherapy. Gemcitabine treatment from week 16 prolonged survival of asbestos-exposed MexTAg mice increasing the median survival from 33 weeks to 48 weeks. Interestingly, latency was not significantly prolonged, but animals survived for longer after the first signs of disease were noted. To understand the importance of the immune system in the pathogenesis of mesothelioma, we crossed MexTAg mice with immune deficient RAG KO mice. Perhaps surprisingly, MexTAg mice with no acquired immunity lived longer with a more indolent disease than their immunocompetent sibs. We compared cell lines derived from mesotheliomas from MexTAg mice and cell lines from wild type mice with human mesothelioma cell lines by expression array. TAg expressing mouse tumours were 90% identical to wild type mouse tumours. The key pathway that was different was cell cycle-associated. Human mesotheliomas commonly have a deletion of the cdkN2 locus, encoding the tumour suppressor genes p16 and p15. While wild type mouse tumours carried a homologous p16 deletion, TAg tumours did not. We hypothesize that TAg expressing mice develop tumours in an accelerated way following asbestos exposure because they are not dependent on deletion of p16 for tumourigenesis. Robinson, C., I. van Bruggen, A. Segal, M. Dunham, A. Sherwood, F. Koentgen, B.W. Robinson, and R.A. Lake. 2006. A novel SV40 TAg transgenic model of asbestos-induced mesothelioma: malignant transformation is dose dependent. Cancer Res 66:10786-10794. Robinson, C., A. Walsh, I. Larma, S. O'Halloran, A.K. Nowak, and R.A. Lake. 2011. MexTAg mice exposed to asbestos develop cancer that faithfully replicates key features of the pathogenesis of human mesothelioma. Eur J Cancer 47:151-161. Robinson, C., S. Woo, A. Walsh, A.K. Nowak, and R.A. Lake. 2012. The antioxidants vitamins A and E and selenium do not reduce the incidence of asbestos-induced disease in a mouse model of mesothelioma. Nutrition and cancer 64:315-322.

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    P1.04 - Poster Session 1 - Tumor Immunology (ID 153)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.04-001 - Combining Prime-Boost Anti-tumour Vaccination with Debulking Surgery for the Treatment of Malignant Mesothelioma (ID 3143)

      09:30 - 16:30  |  Author(s): R. Lake

      • Abstract

      Background
      Malignant mesothelioma (MM) is a highly aggressive cancer with a very poor prognosis. Debulking surgery is often used as the principal therapy but is seldom curative. Adjuvant chemotherapy or radiotherapy can be used as to target residual disease, but these too are largely ineffective, while some early post-surgery immunotherapy strategies had limited clinical success. However, there is renewed interest in the use of immunotherapy to treat MM as new modalities have been developed. Recent work form our laboratory and others, has demonstrated that specific immunotherapies can alert the immune system to the presence of tumour. These therapies are particularly useful when used in conjunction with standard treatment protocols such as surgery or chemotherapy. Here we describe the development of a Prime Boost (P/B) anti-tumour vaccination protocol that when combined with debulking surgery and removal of CD4 T cells improved survival outcome of AB1-HA tumour bearing mice.

      Methods
      Using our established mouse model of mesothelioma, AB1-HA tumour bearing BALB/c mice received influenza A PR/8/34/H1N1 (PR8; Prime) and HA expressing recombinant modified Vaccinia Ankara (rMVA‑HA; Boost) anti‑tumour vaccinations before (neoadjuvant) or after (adjuvant) 75% debulking surgery. Diphtheria toxin (DTX) was administered to tumour bearing BALB/c FoxP3.dtr mice to specifically deplete CD4+ FoxP3+ regulatory T cells (Treg). In both models, tumour growth and overall survival was monitored and immunological parameters assessed by multicolour FACS.

      Results
      Neoadjuvant P/B vaccination alone or in combination with 75% debulking surgery induced a significant increase in splenic tumour‑specific CD8 T cells as well as significant increases in the proportion, activation and proliferation status of peripheral CD8 T cells relative to other treatment groups. However, a significant delay in tumour growth was only observed when neoadjuvant P/B vaccination was combined with debulking surgery. Specific depletion of CD8 T cells demonstrated that they were essential for the delay in tumour growth, although their presence was not sufficient to eliminate the tumour outright. Depletion of CD4 T cells during P/B vaccination enhanced the survival outcome of the surgery + vaccination group with 60% of these mice remaining tumour free for > 60 days post-surgery. Data from preliminary experiments in which Treg in tumour bearing FoxP3.dtr mice resulted in complete tumour regression in 20% of DTX treated mice. Tumour specific immunological memory was confirmed as all surviving mice remained tumour free for at least 60 days post rechallenge with the parental AB1 tumour.

      Conclusion
      Anti-tumour P/B vaccination induced tumour‑specific immunity resulting in delayed tumour growth when combined with debulking surgery. Depletion of CD4 T cells during neoadjuvant P/B vaccination enhanced P/B vaccine efficacy leading to cures in 60% of treated mice. Transient depletion of CD4+ FoxP3+ Treg suggesting that vaccine induced anti‑tumour immunity is “restrained”, possibly by regulatory T cells. Based on these findings we are investigating whether combining novel immunotherapies with conventional treatments in the absence of “immunological restrainers” may generate effective therapy for MM. Financial disclosure: This research was funded by a research grant from the Workers’ Compensation Dust Diseases Board, an agency of the New South Wales Government.

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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 2
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      P1.05-020 - Identifying therapeutic targets for mesothelioma using siRNA (ID 3200)

      09:30 - 16:30  |  Author(s): R. Lake

      • Abstract

      Background
      Mesothelioma is essentially incurable and new drugs to effectively treat it are urgently needed. Our strategy to achieve this aim was to identify candidate mouse and human genes that may have a role in mesothelioma growth and to inhibit their expression in fully transformed mesothelioma cell lines using siRNA.

      Methods
      The initial selection of candidate genes was made on the basis of their differential expression in transcriptome or CGH analyses when comparing malignant to normal mesothelial cells. This was combined with known functional information relevant to tumorigenesis. We also selected a small number of candidates from other published studies. A second set of candidates was chosen from expressed kinases with the idea that these genes are more likely to represent druggable targets given the broad range of kinase inhibitors that are widely available. Where possible, we identified mouse and human homologues of the 40 candidates and then generated both mouse and human siRNA libraries. We tested the effect of gene knockdown on the growth of mouse and human mesothelioma cell lines in vitro.

      Results
      We found knockdown was efficient and inhibition of a subset of the selected genes slowed cell growth significantly across a range of cell lines in both mouse and human systems. There was not complete concordance between the mouse and human: Incenp, Plk1 and Tpx2 were important pathways for murine cellular proliferation; whereas, AURKA, TPX2 and BIRC5 were relevant for human cellular proliferation only. KIF11 was identified in both studies.

      Conclusion
      These genes all have a function in chromosome positioning, centrosome separation and spindle assembly during cell mitosis. Our data show that targeting these gene products in mesothelioma cell line causes growth inhibition both in vitro and in vivo. These studies could provide new leads for drug development.

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      P1.05-021 - Dual checkpoint blockade using anti-PD-1 and anti-CTLA4 combined with cisplatin chemotherapy is effective in a murine mesothelioma model (ID 3214)

      09:30 - 16:30  |  Author(s): R. Lake

      • Abstract

      Background
      Chemotherapy (cisplatin, pemetrexed) remains is the standard of care for mesothelioma (MM) in Australia, however novel immunotherapies are now emerging in clinical trial. Anti-PD-1 (MDX-1106) and anti-CTLA4 (tremelimumab) block different aspects of negative T cell regulation to prolong the activation and survival of anti-tumour cytotoxic T lymphocytes (CTL). While anti-CTLA4 is being tested in Phase II clinical trial, the efficacy of anti-PD-1 in MM patients is yet to be determined. The notion of combining chemo-immunotherapy has gained ground in recent years with the discovery that chemotherapy-induced tumour cell death can be immunogenic, and thus exploited with the right immunotherapy drug.

      Methods
      The murine mesothelioma line generated in our lab, AB1-HA, was inoculated subcutaneously into the flanks of Balb/c mice. Tumour growth and survival following treatment with anti-PD-1 and/or anti-CTLA4, plus chemotherapy (gemcitabine, cisplatin) was monitored. Tissues (spleen, lymph nodes) were harvested at various time-points for flow cytometric analaysis to investigate immune correlates of response.

      Results
      Dual checkpoint blockade (anti-CTLA4 + anti-PD-1) was effective at delaying tumour outgrowth and improving survival, over either treatment alone (anti-PD-1 had negligible effect on AB1-HA growth). Combining this with cisplatin chemotherapy achieved an even greater effect, however this was not the case with gemcitabine.

      Conclusion
      The effect of dual checkpoint blockade mirrors that which has recently been discovered in mouse models of melanoma [1]and colon cancer [2]. The ability to combine this with chemotherapy to our knowledge has not been previously identified. Furthermore, it is interesting that the triple combination was only successful with cisplatin rather than gemcitabine, which in our hands has been shown to be immunogenic and works synergistically with other immunotherapies, such as anti-CD40. Not only can this finding be directly translated to the clinic, it also prompts future investigation into how best to combine different therapies to tackle malignancies that may be refractory to standard monotherapy treatments. 1. Curran, M.A., et al., PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A, 2010. 107(9): p. 4275-80. 2. Duraiswamy, J., et al., Dual Blockade of PD-1 and CTLA-4 Combined with Tumor Vaccine Effectively Restores T-Cell Rejection Function in Tumors. Cancer Res, 2013. 73(12): p. 3591-603.

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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: 2
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      P2.05-020 - Combined gemcitabine and anti-CTLA4 therapy to target residual tumour following partial debulking surgery in a mouse mesothelioma model (ID 3206)

      09:30 - 16:30  |  Author(s): R. Lake

      • Abstract

      Background
      Complete surgical resection of solid malignancies is often not achieved due to growth of occult tumour cells, distant metastases, or the invasiveness of the tumour mass. Hence there is a need for adjuvant therapies that may be administered following surgery to target residual tumour. Using a murine mesothelioma model we have previously shown that combining gemcitabine with anti-CTLA4 is effective at generating an anti-tumour immune response, leading to tumour regression and improved survival. We sought to use this treatment regimen to improve the post-surgical outcome of debulking surgery.

      Methods
      The murine mesothelioma line generated in our lab, AB1-HA, was inoculated subcutaneously into the flanks of Balb/c mice. Established tumours (<50mm[2]) were debulked by surgical removal of 75% of the tumour mass. Treatment with gemcitabine and anti-CTLA4 were commenced on the day of surgery, and mice were monitored for residual tumour outgrowth and survival. Size-matched controls were treated in parallel.

      Results
      Dual administration of gemcitabine with anti-CTLA4 was effective at causing regression of remaining tumour and improving survival following partial debulking surgery, over either therapy alone. The outcome of this treatment when administered to debulked tumours was comparable to that achieved against smaller, size-matched tumours.

      Conclusion
      We have shown that larger tumours can be successfully partially debulked and the remaining tumour treated using a combination of gemcitabine and anti-CLTA4. Thus, combined chemo-immunotherapy is a feasible option for post-surgical treatment option to remove residual tumours.

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      P2.05-021 - Molecular analysis of asbestos-induced mesotheliomas from SV40 TAg transgenic mice shows that they are highly concordant with human mesothelioma (ID 3211)

      09:30 - 16:30  |  Author(s): R. Lake

      • Abstract

      Background
      Asbestos-induced mesothelioma in MexTAg transgenic mice closely resembles the key features of human disease. This model is highly suited to testing new chemotherapies and cancer prevention strategies. The resultant mesothelioma responds to cytotoxic chemotherapy with efficacy of the same order of responsiveness as human mesothelioma. The transgene, large T Antigen is an oncogene encoded by Simian Virus 40, and the role of this viral oncogene in tumourigenesis has been widely studied. Here we investigate the gene expression differences between TAg tumours and wild type tumours and examine overall similarity to human mesothelioma at the molecular level.

      Methods
      not applicable

      Results
      We found TAg expressing mouse tumours were 90% identical to wild type mouse tumours. The key pathway that was affected by these gene differences was cell cycle. Gene set enrichment analysis showed that the TAg:wild type tumour differences were homolgous to the Rb null genotype in a TAg dose dependent manner. To address whether transgenic mouse tumours were a good representation of human mesothelioma when compared to wild type mouse tumours, we showed that of genes differentially expressed between i) TAg or ii) wild type mouse tumours and mouse mesothelial cells, there were the same number of gene similarities with the set of genes that differentiate between human mesothelioma and human mesothelial cells. Human mesotheliomas commonly have a deletion of the cdkN2 locus, encoding the tumour suppressor genes p16 and p15. We found that while wild type mouse tumours contained the p16 deletion, TAg tumours did not.

      Conclusion
      In summary, the asbestos-induced mesotheliomas in MexTAg mice are comparable to human mesothelioma at the molecular level. We hypothesize that TAg expressing mice develop tumours in a more uniform way than wild type mice following asbestos exposure and are not dependent on deletion of p16 for tumourigenesis.

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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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      P2.10-041 - Optimising regulatory T cell (Treg) depletion in combination with chemotherapy for enhanced anti-tumour immunity (ID 2576)

      09:30 - 16:30  |  Author(s): R. Lake

      • Abstract

      Background
      Cytotoxic chemotherapy is widely used to palliate malignant pleural mesothelioma (MM) and non small cell lung cancer (NSCLC). While originally considered detrimental to the immune system, there is now abundant preclinical data showing that chemotherapy can enhance anti-cancer immunotherapy. Tregs are immunosuppressive CD4[+] T cells thought to inhibit anti-tumour immune responses; murine data suggests that Treg eradication may augment existing anti-tumour immunity. Cyclophosphamide (CTX) is immunostimulatory and at low doses selectively depletes Tregs in mice and humans. The primary objective of this study is to identify an optimum dose and schedule of iterative low dose oral CTX for Treg depletion in the context of pemetrexed-based chemotherapy, and to determine how treatment affects the function and phenotype of the cellular immune response.

      Methods
      In this single centre phase 1b study we investigate an optimum dose and schedule of iterative low dose oral CTX for Treg depletion, in the context of pemetrexed-based chemotherapy, and how treatment affects the function and phenotype of the cellular immune response. Thirty-one patients with advanced malignant pleural mesothelioma (MM) or non-small cell lung cancer (NSCLC) received standard doses of pemetrexed ± cisplatin or carboplatin on a 21 day schedule (6 cycles max.). From the second cycle, escalating doses of oral CTX were administered, initially with 50 mg daily. Weekly peripheral blood samples were collected, and the proportion of Tregs within the CD4[+] population (Treg%) determined by flow cytometry, amongst other immunological parameters.

      Results
      31 participants enrolled on the study (27 MM, 4 NSCLC). The mean number of treatment cycles completed was 4.2 from a potential total of 6 cycles, with 20 participants on-study for at least 4 cycles, and the combination was safe and feasible. Contrary to our initial hypothesis, CTX treatment did not reduce the Treg proportion of CD4[+] T cells in peripheral blood, with baseline Treg (CD127[lo]CD25[+]Foxp3[+]) proportion of CD4+ T cells at 4.44±1.56% and no significant change observed when comparing values from the end of each treatment cycle. Doses above 50/100 mg did not improve depletion. However, analysis of the T-effector cell population has demonstrated an increased frequency of CD38[hi]HLA-DR[hi] cells within the total CD8[+] T cell pool. From the perspective of biological relevance, the ratio of activated T-effector cells to Tregs changes minimally during the first cycle of standard care chemotherapy (baseline = 0.21±0.15 T-effectors per Treg); however, from mid-way through cycle 2 (when CTX treatment begins) onward a notable and variable increase in the proportion of activated T-effector cells is observed (end of cycle 3 = 2.21±3.83 T-effectors per Treg). Detailed immunological data will be presented.

      Conclusion
      These data suggests that CTX with chemotherapy can increase the proportion of activated T-effector cells, an observation that has the potential to improve anti-tumour immunity or chemo-immunotherapy efficacy. We postulate that CTX may affect the function rather than numbers of Treg cells, decreasing their ability to suppress the proliferation of CD8+ effector T cells.

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    P2.14 - Poster Session 2 - Mesothelioma (ID 196)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P2.14-004 - EORTC and CALGB prognostic models, but not neutrophil-to-lymphocyte ratio, are prognostic in unselected patients with newly diagnosed malignant mesothelioma (ID 1259)

      09:30 - 16:30  |  Author(s): R. Lake

      • Abstract

      Background
      Neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, was proposed as a prognostic biomarker in a number of malignancies, including malignant pleural mesothelioma (MPM). We examined baseline variables predictive of overall survival (OS) in patients with newly diagnosed MPM, including NLR and the established EORTC and CALGB prognostic models.

      Methods
      Consecutive patients with newly diagnosed MPM between 1[st] January 2005 and 31[st] December 2010 at Sir Charles Gairdner Hospital, Western Australia were included in this retrospective study. Eligible patients had a confirmed diagnosis of MPM, neutrophil and lymphocyte count within 90 days of diagnosis, no concurrent haematological malignancy, and follow-up more than 90 days from diagnosis. Any subsequent treatment, including supportive care alone, was allowed. Variables to be analysed and cut-off determination was predetermined according to previous reports. Multiple imputation was performed for missing values, and univariate analyses and multivariate Cox models were calculated for OS.

      Results
      274 of 369 patients screened met the eligibility criteria and were included in this retrospective study. 159 received systemic chemotherapy, 10 underwent tri-modality therapy; 2 underwent surgery only, and 103 received supportive care alone. Prognostic factors predictive of shorter survival in univariate analysis were: age ≥ 65 years, non-epithelioid histology, sarcomatous histology, AJCC stage III-IV, ECOG performance status (PS) 2-3, weight loss, chest pain, low haemoglobin and high platelet count. An NLR ≥ 5 at diagnosis did not predict for shorter OS (hazard ratio (HR) 1.25; p=0.122). On multivariate analysis, age, histology, PS, weight loss, chest pain, and platelet count remained significant. The EORTC and CALGB prognostic groups were highly statistically significant as predictors for OS (HR 1.62; p<0.001 and HR 1.65; p<0.001, respectively). On preplanned subgroup analyses, baseline NLR was not prognostic in chemotherapy-treated or non-chemotherapy treated patients.

      Univariate and multivariate analyses of association of prognostic factors with overall survival
      Univariate analysis Multivariate analysis
      Baseline prognostic factor HR (95% CI) P-value HR (95% CI) P-value
      Baseline NLR <5* vs. ≥5 1.25 (0.94-1.66) 0.122 1.02 (0.76-1.37) 0.893
      Age <65* vs. ≥65 years 1.64 (1.24-2.17) <0.001 1.41 (1.05-1.90) 0.023
      Female* vs. Male 1.23 (0.86-1.77) 0.262 1.24 (0.85-1.81) 0.269
      Epithelioid* vs. non-epilthelioid 1.40 (1.08-1.80) 0.009 1.38 (1.05-1.82) 0.023
      Non-sarcomatous* vs. sarc. 2.37 (1.62-3.48) <0.001 1.86 (1.22-2.84) 0.004
      AJCC Stage I-II* vs. III-IV 1.52 (1.17-1.97) 0.002 1.27 (0.97-1.66) 0.087
      ECOG PS 0-1* vs. 2-3 2.35 (1.59-3.46) <0.001 1.81 (1.21-2.70) 0.004
      Weight loss absent* vs. present 2.11 (1.62-2.74) <0.001 1.62 (1.22-2.15) <0.001
      Chest pain absent* vs. present 1.58 (1.21-2.07) <0.001 1.34 (1.02-1.76) 0.038
      Hb difference <10* vs. >10 1.87 (1.41-2.49) <0.001 1.32 (0.96-1.80) 0.087
      WCC (x 10[9]/L) ≤8.30* vs. >8.30 1.22 (0.96-1.57) 0.110 0.95 (0.73-1.25) 0.745
      PLT (x 10[9]/L) ≤400* vs. >400 1.96 (1.49-2.58) <0.001 1.71 (1.26-2.33) <0.001
      Abbreviations: *=referent; AJCC=American Joint Committee on Cancer Staging System; ECOG= Eastern Cooperative Oncology Group, WCC=White cell count; NLR=Neutrophil-to-lymphocyte ratio

      Conclusion
      Our findings validate established baseline prognostic variables as well as the EORTC and CALGB models, but not baseline NLR in unselected patients with newly diagnosed MPM. In guiding treatment decisions for patients at time of diagnosis, multiple variables should be considered that jointly predict survival

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    P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.05-020 - Strategies for the prevention of mesothelioma in MexTAg mice (ID 3205)

      09:30 - 16:30  |  Author(s): R. Lake

      • Abstract

      Background
      Current treatments for mesothelioma typically increase median survival by a matter of months. Progress in treatment has been hampered by lack of a suitable small animal model, which could guide clinical advances, given limited numbers of patients eligible for clinical trials. To this end we recently developed a transgenic mouse model of mesothelioma in which the viral oncogene, SV40TAg (TAg) is directed to mesothelial cells by use of the cell type specific mesothelin promoter. MexTAg mice develop mesothelioma rapidly and uniformly, but only following exposure to the natural carcinogen, asbestos. The model closely mimics the human disease and is thus ideal for both rapid analysis of novel therapeutic studies and for investigating factors that might act synergistically with asbestos to cause disease. Since all MexTAg mice develop mesothelioma following asbestos exposure the model is highly suitable for early intervention and cancer prevention studies. An effective cancer prevention strategy for the millions of people who have been exposed to asbestos could have enormous benefit worldwide. Epidemiological evidence indicates that supplementation with some dietary factors or use of common drugs such as statins and non-steroidal anti-inflammatory drugs is associated with a lower incidence of cancer.

      Methods
      not applicable

      Results
      We previously reported that dietary supplementation with a number of antioxidants did not alter the time to develop disease nor overall survival, despite the widely accepted hypothesis that asbestos catalyzed production of reactive oxygen and nitrogen species contribute to the development of this cancer. We have extended these studies to test whether vitamin D, non-steroidal anti-inflammatories, statins and some other candidate diets could alter the pattern of disease in the MexTAg model. Supplemented diets were provided at levels based on published data and began 2 weeks prior to asbestos exposure in order to maximize our chance of detecting a benefit. Preliminary data suggests a single agent or nutraceutical may not be enough to prevent the multiple pathways involved in tumorigenesis. This is somewhat supported by epidemiological data from the Wittenoom cohort of asbestos exposed workers and residents.

      Conclusion
      In conclusion, we think it is unlikely that antioxidants, anti-inflammatories or other nutrient-specific dietary supplements will moderate the rate of mesothelioma in asbestos exposed populations.