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    PC 01 - 1-1. Surgery vs Non-Surgical Local Treatment for Small-Sized NSCLC (ID 581)

    • Event: WCLC 2017
    • Type: Pros & Cons
    • Track: Early Stage NSCLC
    • Presentations: 3
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      PC 01.01 - SABR as First Line Treatment Option (ID 7822)

      15:45 - 16:45  |  Presenting Author(s): Hak Choy

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Surgery has historically been the primary treatment option for patients with Stage I non–small-cell lung cancer (NSCLC). Although Stage I NSCLC is technically curable, the presence of significant co morbidity increases the risk of postoperative complications and reduces the potential role of surgery even early stage NSCLC. Because nonsurgical treatment options such as conventional radiotherapy have historically achieved suboptimal outcomes, some have argued that the risks associated with surgery in patients with severe COPD were justified. The reason for poor tumor control with conventional radiation therapy has been shown to be due to insufficient total radiation doses which is usually 60 Gy or lower. Dose escalation with CRT have shown that a total dose of just above 80 Gy seems to be tolerable while doses exceeding 90 Gy, necessary for optimal tumor control, were associated with high risk of unacceptable lung toxicity. Since the 2000s, stereotactic body radiation therapy has rapidly spread as medical physics improved. Stereotactic body radiation therapy has been revealed to be equivalent to surgery in tumor ablation. With stereotactic body radiotherapy (SBRT) the radiation dose to normal tissue is minimized and the dose per fraction can be increased resulting in biologic doses up to twice as high as in CRT. This has resulted in improvement of local tumor control rates up to 88% to 100%, comparable to the rates after surgery. SBRT is a safe and effective treatment option for these patients, with outcomes that do not appear to be inferior to surgery. SBRT is not associated with the considerable initial risks of operative mortality and prolonged hospitalization. Patients who do undergo surgery may benefit from avoiding open lobectomy, instead using less invasive approaches such as video-assisted thoracoscopic surgery or open segmentectomy. All patients with Stage I NSCLC and severe COPD should be evaluated in a multidisciplinary setting and afforded an informed decision of the risks and benefits of both surgery and SBRT. In role of SBRT can also be extended even in patients with oligometastases and oligo-recurrence, the oligometastases and oligo-recurrence who sometimes cured with only local therapy. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor-specific T-cells, acting as an in situ tumor vaccine; however, SBRT alone has limit in inducing effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement SBRT to help overcome tumor-induced immune suppression, as demonstrated in many pre-clinical tumor models. There are many trials underway for combinations of different immunotherapies and SBRT.

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      PC 01.02 - Surgery as First Line Treatment Option (ID 7823)

      15:45 - 16:45  |  Presenting Author(s): Robert John Downey

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Surgery as First Line Treatment Option for Small-Sized NSCLC Surgical resection has been the preferred standard of care for patients with well established expectations for survival after resection. A standard of care for patients who are deemed medically inoperable is definitive radiation therapy. Because of the proven effectiveness of radiation therapy in treating the medically inoperable patient with lung cancer, consideration is being given to treating medically operable lung cancer patients with definitive radiation therapy instead of surgery. However, recent clinical guidelines issued by ASTRO (Videtic et al) based on a review of the published data include among other recommendations, that ‘For stage I NSCLC patients with anticipated risk of operative mortality of <1.5%, SBRT is not recommended as an alternative to surgery outside of clinical trial settings. The recommended treatment for these patients remains lobectomy with systematic mediastinal lymph node evaluation’. The problem with such recommendations is as follows. The operative morbidity and mortality following pulmonary resection for the overall population of patients undergoing surgery have also been established. The morbidity and mortality in the overall population of patients following definitive radiation therapy is also well documented. What is not available is reliable data on the treatment-related risks faced by subgroups of patients treated with surgery or with definitive chemotherapy who differ in terms of competing risk factor for death, including age (Eguchi et al.) or their overall functional status ((or what is becoming known as the ‘fitness’ or conversely, the ‘frailty’ of a patient) Korc et al)). Emerging data shows that the frailty of a patient affects the likelihood of survival after surgery of diverse types and for diverse diseases. We have found that frail patients undergoing diverse surgeries for diverse malignancies require ICU admission after a given grade of complication at rates far above those required for fit patients (after Grade I complication 0% vs 20%, after Grade 2 complication 6% vs. 17%, and after Grade 3 complication 5% vs. 35% for fit vs. frail respectively) After ICU admission, frail patients remain at a persistent increased risk of death lasting at least to 600 days when compared to fit patients (50% survival vs. 90% survival for frail patients vs. fit patients after ICU care at 600 days) (unpublished data courtesy of Armin Sharokhni, MD). Similar data is not available for patients with NSCLC treated with definitive radiation therapy. Because of this lack of information, objective comparisons of the feasibility and effectiveness of surgical resection with definitive radiation therapy are likely prone to error due to selection biases.A plausible hypothesis is that the population of patients referred for definitive radiation therapy for NSCLC are frailer, and the decreased long-term survival after radiation therapy is due to frailty rather than cancer-related. In this talk, we will review the data available on: 1. Current perioperative morbidity and mortality following lung resections including MIS and sub-lobar procedures 2. Current likelihood of long-term survival following curative lung cancer surgery 3. The competing risks for short- and long-term survival after surgery including age and frailty 4. The methods of risk stratification, including frailty, for a patient being considered for lung cancer surgery 5. The methods of risk stratification that have been used in retrospective and prospective comparisons of surgery and definitive radiation therapy Based on this review, proposals for prospective trials comparing SBRT and surgery for objectively defined medically operable early stage NSCLC will be made. References: Eguchi et al. Impact of Increasing Age on Cause-Specific Mortality and Morbidity in Patients With Stage I Non-Small-Cell Lung Cancer: A Competing Risks Analysis. J Clin Oncol. 2017;35:281-290 Korc-Grodzicki et al. Surgical considerations in older adults with cancer. J Clin Oncol 2014;32:2647-53.. Videtic et al. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Practical Radiation Oncology (in press)

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      PC 01.03 - Other First Line Treatment Options (ID 7824)

      15:45 - 16:45  |  Presenting Author(s): Hiran Fernando

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The approach that has most commonly been reported as an alternative to surgery or SBRT for non-small lung cancer (NSCLC) is thermal ablation. There are also different ablative modalities, of which radiofrequency ablation (RFA) has been the most widely reported. RFA was reported for human lung tumors in 2000 [1]. RFA has been shown to be feasible and safe in several studies[2,3]. However, many studies have involved heterogeneous patient populations that included patients with metastatic tumors and NSCLC. Additionally, in those series focusing on NSCLC, patients with different stages. Have been included. Another consideration is that in several centers, these procedures have been performed by interventional radiologists, who are not traditionally part of the multidisciplinary oncology team, and rarely have follow-up clinics, so accurate reporting of recurrence and survival rates has not been optimal. Lastly, other modalities such as microwave or cryoablation, are gaining in popularity [4],[5] Despite some perceived improvements in technology, there is no clinical data that supports one ablative modality over another with respect to cancer outcomes[6] . Currently thermal ablation is reserved for medically inoperable patients with NSCLC. In those series that have reported outcomes specifically for stage I NSCLC outcomes have been good, and comparable with studies of SBRT, when looking at survival rates. One study included 56 patients with stage I NSCLC[7]. Median survival was 29 months. A prospective multi-center phase II trial involving 54 patients was recently reported[8]. Overall survival was 87.3% at 1-year, and 69.8% at two-years. Two-year survival was superior in patients with tumors <2cm (83%). There were only two grade 4, and one grade 5 event within 90 days (not attributable to the RFA). Our group has also treated 21 patients with stage Ia NSCLC (submitted for publication). Three-year survival in our series was 52%. One issue when comparing results of trials using different modalities is how comparable are patient groups. The medically inoperable group in this prospective phase II trial were compared to a medically group in an RTOG phase II trial of SBRT[9]. Although both groups were labelled medically inoperable, lung function was significantly better in patients treated with SBRT. This argues for the need for prospective studies comparing these modalities for medically inoperable patients. The main issue with thermal ablation has been higher rates of local recurrence in most studies. Tumor size is important, and results are better for tumors <2cm[7,8]. This certainly would be an argument for SBRT over RFA. However how recurrence is measured and defined may impact on reporting of local control, and there are differences in how these have been identified in different studies. In the absence of a prospective trial using similar end-point recording, overall survival is the cleanest endpoint with which to make comparisons. In summary, thermal ablation remains a viable option for small stage I NSCLC patients who are deemed medically inoperable. Future innovations include developments in energy source and, also in bronchoscopic delivery to peripheral tumors[10]. References 1. Dupuy DE, Zagoria RJ, Akerley W, et al: Percutaneous radiofrequency ablation of malignancies in the lung. AJR Am J Roentgenol 174:57-9, 2000 2. Ambrogi MC, Fanucchi O, Cioni R, et al: Long-term results of radiofrequency ablation treatment of stage I non-small cell lung cancer: a prospective intention-to-treat study. J Thorac Oncol 6:2044-51, 2011 3. Lencioni R, Crocetti L, Cioni R, et al: Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). Lancet Oncol 9:621-8, 2008 4. Zhong L, Sun S, Shi J, et al: Clinical analysis on 113 patients with lung cancer treated by percutaneous CT-guided microwave ablation. J Thorac Dis 9:590-597, 2017 5. Ahrar K, Littrup PJ: Is cryotherapy the optimal technology for ablation of lung tumors? J Vasc Interv Radiol 23:303-5, 2012 6. Vogl TJ, Nour-Eldin NA, Albrecht M, et al: Thermal Ablation of Lung Tumors: Focus on Microwave Ablation. Rofo, 2017 7. Simon CJ, Dupuy DE, DiPetrillo TA, et al: Pulmonary radiofrequency ablation: long-term safety and efficacy in 153 patients. Radiology 243:268-75, 2007 8. Dupuy DE, Fernando HC, Hillman S, et al: Radiofrequency ablation of stage IA non-small cell lung cancer in medically inoperable patients: Results from the American College of Surgeons Oncology Group Z4033 (Alliance) trial. Cancer 121:3491-8, 2015 9. Crabtree T, Puri V, Timmerman R, et al: Treatment of stage I lung cancer in high-risk and inoperable patients: comparison of prospective clinical trials using stereotactic body radiotherapy (RTOG 0236), sublobar resection (ACOSOG Z4032), and radiofrequency ablation (ACOSOG Z4033). J Thorac Cardiovasc Surg 145:692-9, 2013 10. Koizumi T, Tsushima K, Tanabe T, et al: Bronchoscopy-Guided Cooled Radiofrequency Ablation as a Novel Intervention Therapy for Peripheral Lung Cancer. Respiration 90:47-55, 2015

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    PC 01 - 1-2. What is the Role of Local Therapy in Non-CNS Oligometastatic NSCLC? (ID 592)

    • Event: WCLC 2017
    • Type: Pros & Cons
    • Track: Advanced NSCLC
    • Presentations: 2
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      PC 01.04 - There is a Role of Surgery in Non-CNS Oligometastatic Disease (ID 7825)

      16:45 - 17:30  |  Presenting Author(s): Young Tae Kim

      • Abstract
      • Presentation
      • Slides

      Abstract:
      For certain extra-pulmonary malignancies, such as colorectal cancer or sarcomas, the existence of curable oligometastatic disease state has been well established. Oligometastasis is a state of stage IV disease associated with limited spread of disease at the time of diagnosis. This condition may reflect a more indolent phenotype than that associated with more widespread disease at presentation. Recently, it becomes more clear that the patients with Stage IV NSCLC are heterogenous and hence, some patients have high disease burden whereas others have isolated metastatic lesions. In the 8th TNM staging system, M-stage was reclassified into M1a, M1b, M1c, and the patients with M1b may represents the oligometastatic status of NSCLC. It has been demonstrated that the predominant pattern of failure in patients with oligometastasis treated with the first-line systemic chemotherapy was mainly a local failure, the fact which leads an idea that the local treatment may improve cure rates in such patients. The incidence of oligometastasis in NSCLC has been reported 7-26% of NSCLC [1, 2], with the major sites of metastases being bone, brain, adrenal glands and liver. In general, the successful treatment of patients with oligometastasis requires the ability to eradicate the primary site, the ability to image all sites of metastatic disease, the ability to ablate all metastatic sites, and having effective systemic therapy to eradicate undetected micrometastatic disease. Recently, routine use of improved diagnostic imaging tools such as PET-CT or Brain MRI, can better detect latent metastases in patients who would otherwise have been thought to have a localized disease, and hence, the diagnosis of “true” oligometastatic disease may be increasing [3]. Development of local treatment modalities such as minimally invasive surgery (MIS) or stereotactic radiotherapy (SABR) enabled effective local abrasion of the metastatic sites without major morbidities. Above all, rapid development of effective molecular target agents and immune check point agents in the treatment of NSCLC are encouraging to reconsider surgery for the treatment of oligometastatic NSCLC patients. Most evidence of treatment effect of local treatment for oligometastasis derives from the survival data from retrospective patients groups. For brain metastases, 5-year survival rates have been reported 6.6-35% and adrenal gland metastases showed similar results (5-year survival rates 12-40%). In a well-designed propensity score matching study suggested an improvement in survival favoring local abrasive therapy, but definite conclusions on the efficacy of local therapy for the treatment of extra-cranial oligometastatic NSCLC could not be reached [4]. A meta-analysis which included 49 studies, suggested overall median overall survival of 19 months after local ablative treatment (5.9-52 months)[5]. Most recent study by Gomez and colleagues demonstrated a progression free survival benefit favoring local consolidative therapy [6]. Hopefully, ongoing prospective trials may provide more strong evidence of the effect of local ablative therapy for oligometastasis in near future. Despite many reports that support local treatment for oligometastasis, the lack of control data in almost all reports is a problematic issue. Since local treatment for the oligometastasis is only performed in selected patients with relatively indolent disease, there is often no actual denominator for the entire group of patients who developed metastasis [7]. Thus, determining the survival advantage of ablative local treatment of oligometastasis compared to palliative systemic therapy is difficult because the majority of existing data are with a substantial degree of selection bias. In the other aspect, however, we have learned that the patient selection is critical for the application of local treatment on the oligometastasis. In general, local treatment is indicated in metastatic NSCLC patients with favorable prognostic factors including absence of mediastinal lymph node metastasis, small number of metastases, complete control of primary lesion, meta-chronous metastasis, and good performance status of the patients. Although there are relatively large numbers of papers on the brain or adrenal metastases, the reports of extra-cranial or extra-adrenal metastases are rare. In a meta-analysis, the 5 year overall survival rates of extra-cranial / extra-adrenal metastasis was 50% and the prognosis was mainly influenced by lymph node metastasis status[ 8]. First used in the literature in 2012 [9], the concept of oligoprogressive disease has been rapidly adopted. It can be best described in patients with tumors harboring actionable mutations who are treated with molecular targeted therapies. Initially, the response rate is great but the duration of response is relatively short, with resistance to therapy generally emerging within a year of start of treatment as a result of various genetic mechanisms. Not uncommonly, disease progression during molecular targeted therapy occurs at a limited number of anatomic sites. Recently, several studies reported improved progression free survival and overall survival in either intra-cranial or extra-cranial oligopregressive diseases by applying local abrasive therapy on those acquired resistant oligoprogressive diseases and by resuming target agents [10]. Furthermore, the combination of immune check point agents and SABR on primary tumor and/or metastatic sites may be promising for treating oligometastatic NSCLC, due to a possible abscopal effect. In conclusion, although current evidence of local treatment of oligometastases is limited in NSCLC, with aid of recent diagnostic tools by which more stringent patient selection is possible, local ablative treatment of metastatic lesions can lead improved survival of patients with oligometastasis in conjunction with molecular target agents or immune check point agents. 1. Albain KS, Crowley JJ, LeBlanc M, et al. Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1991;9:1618-1626. 2. Parikh RB, Cronin AM, Kozono DE, et al. Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer. International journal of radiation oncology, biology, physics 2014;89:880-887. 3. Tonnies S, Tonnies M, Kollmeier J, et al. Impact of preoperative 18F-FDG PET/CT on survival of resected mono-metastatic non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 2016;93:28-34. 4. Sheu T, Heymach JV, Swisher SG, et al. Propensity score-matched analysis of comprehensive local therapy for oligometastatic non-small cell lung cancer that did not progress after front-line chemotherapy. International journal of radiation oncology, biology, physics 2014;90:850-857. 5. Ashworth A, Rodrigues G, Boldt G, et al. Is there an oligometastatic state in non-small cell lung cancer? A systematic review of the literature. Lung cancer (Amsterdam, Netherlands) 2013;82:197-203. 6. Gomez DR, Blumenschein GR, Jr., Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. The Lancet Oncology 2016;17:1672-1682. 7. Fiorentino F, Treasure T. Pulmonary metastasectomy: a call for better data collection, presentation and analysis. Future oncology (London, England) 2015;11:19-23. 8. Salah S, Tanvetyanon T, Abbasi S. Metastatectomy for extra-cranial extra-adrenal non-small cell lung cancer solitary metastases: systematic review and analysis of reported cases. Lung cancer (Amsterdam, Netherlands) 2012;75:9-14. 9. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2012;7:1807-1814. 10. Iyengar P, Kavanagh BD, Wardak Z, et al. Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2014;32:3824-3830.

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      PC 01.05 - There is No Role of Surgery in Non-CNS Oligometastatic Disease (ID 7826)

      16:45 - 17:30  |  Presenting Author(s): Egbert F Smit

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    P1.14 - Radiotherapy (ID 700)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Radiotherapy
    • Presentations: 1
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      P1.14-005 - Development of a Novel Spacer to Reduce Mediastinal Organ Toxicity from Stereotactic Body Radiotherapy (ID 7447)

      09:30 - 16:00  |  Author(s): H. Date

      • Abstract
      • Slides

      Background:
      Recently, stereotactic body radiotherapy (SBRT) has become available for patients who are at high risk for lung resection. Although SBRT for peripheral lung tumors produces excellent outcomes with low toxicity, it is associated with an increased risk of severe toxicity when used to treat central tumors. We hypothesized that using a spacer designed to provide a predetermined distance between the target lesion and mediastinal organs may reduce adjacent organ toxicity, thereby expanding the indication of SBRT for lung cancer.

      Method:
      We developed a novel silicon-based spacer that imitated the shape of a canine’s left mediastinum. Animal experiments were performed on canine models to evaluate the feasibility, utility, and safety of the spacer. Two adult beagle dogs were used in this study. Video-assisted thoracoscopic surgery (VATS) was performed through two ports to insert the spacer between the lung and mediastinum of the left thoracic cavity. CT examination was performed with the spacer inflated at 1 week and 2 weeks after insertion. Four weeks after insertion, the spacer was removed. We created two virtual tumors that presented a high risk of severe mediastinal organ toxicity from SBRT. Radiation treatment planning of SBRT was conducted in both cases, and the radiation dose for mediastinal organs was compared between the cases with and without the spacer.

      Result:
      The spacer could be safely inserted between the lung and mediastinum via the VATS procedure. The novel spacer provided a distance of 5-10 mm between the virtual tumor and the mediastinal organs. The reduced radiation dose for risk organs were calculated as 7.0-27.5% in the aorta, 3.0-12.3% in the esophagus, and 7-25% in the spine. The spacer did not adhere to the mediastinal organs, and was removed smoothly. Figure 1



      Conclusion:
      The novel mediastinal spacer may potentially reduce mediastinal organ toxicity from SBRT when treating centrally located lung tumors.

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    P3.02 - Biology/Pathology (ID 620)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 2
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      P3.02-046 - EGFR-Grb2-GEP100 Complex Promoted Its Invasive and Metastatic Potential via Arf6 Pathway in Lung Adenocarcinoma (ID 9546)

      09:30 - 16:00  |  Author(s): H. Date

      • Abstract

      Background:
      Invasive and metastatic activities are the most challenging hallmark of cancer. We previously showed that GEP100-Arf6 pathway signals from stimulated ErbB family receptors was pivotal for epithelio-mesenchymal transition (EMT) and induced cancer invasive activity leading to nodal and distant metastasis. Here we have examined the enhancing effect of Grb2 on the binding of GEP100 with EGFR leading to Arf6 activation and EMT, and the significance of EGFR-Grb2-GEP100 binding complex on the invasive and metastatic potentials in lung cancer cells as well as in clinical settings.

      Method:
      A549 lung cancer cells with overexpressed HA-tagged Grb2 or HA alone were stimulated with EGF, and the lysates were applied for the immunoprecipitation assay against GEP100. Arf6 activities of these cells were examined using the pulldown assay with GST-tagged GGA protein. In vitro invasive activities of those cells were measured by Matrigel invasion assays. To clarify the mutual binding sites between Grb2 and GEP100, GST-tagged proteins including Plekstrin homology (PH) domain of GEP100 or SH2/SH3 domain of Grb2 inserted into pGEX vector were produced in bacteria with glutathione-beads purification. Furthermore, mutant Grb2-R86K which impairs the binding to pEGFR was transfected into A549 cells to examine the changes of the binding affinity between pEGFR and GEP100. Last, we performed immunohistochemistry against Grb2, GEP100, and phosphorylated receptor tyrosine kinases (pRTKs) comprising EGFR, Her2, c-Met, and VEGFR, which have been known to bind GEP100 leading to Arf6 activation, for 239 cases of primary lung adenocarcinoma specimens resected in our hospital. The expression of these molecules integrated with the clinicopathologic data and EMT status information were statistically analyzed.

      Result:
      Grb2 overexpression via Grb2-GEP100 interaction promoted EGFR-GEP100 binding leading to Arf6 activation and tumor invasive activity in A549 cells. PH domain of GEP100 and N-terminal SH3/SH2 domain of Grb2 were contributed to this binding. Mutant Grb2-R86K exogenous expression in A549 cells resulted in the decrease of the binding between pEGFR and GEP100. Among 155 cases of positive pRTKs, the combination of Grb2 and GEP100 positivity were significantly associated with activated EMT levels, node metastasis, and poor disease-free survival (p=0.048, p=0.08, and p=0.0075, respectively).

      Conclusion:
      EGFR-Grb2-GEP100 complex promoted its invasive and metastatic potential via Arf6 pathway in lung adenocarcinoma. The inhibition of the binding among these molecules may be useful to control lung cancer progression.

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      P3.02-071 - Statins May Improve the Prognosis of Patients with Lung Adenocarcinoma by Suppressing Mutant p53-Induced EMT (ID 9152)

      09:30 - 16:00  |  Author(s): H. Date

      • Abstract

      Background:
      Epithelial-mesenchymal transition (EMT) is known to be pivotal for driving metastasis and recurrence in lung cancer. Some reports have shown statins suppressed EMT by inactivating mutant p53 functions in vitro. Although several clinical trials regarding conventional treatments with statins have been performed, the effect of statins on the prognosis is still controversial. The purpose of the present study is to clarify the impact of statins on EMT and the prognosis of patients with lung adenocarcinoma harboring p53 mutation.

      Method:
      Firstly, we transfected wild type p53 or mutant p53 (R175H, R273H) to H1650 cells and administrated simvastatin. We evaluated morphological changes by microscopic measurement and analyzed EMT markers (E-cadherin, vimentin) through western blotting of whole cell lysate. We also analyzed their invasive ability through Matrigel invasion assay. Secondly, a total of 282 lung adenocarcinoma specimens were collected from patients who underwent surgery in our institute from January 2001 to December 2007. We analyzed EMT markers through immunostaining of tumor specimens and we determined p53 mutation by single stranded conformational polymorphism followed by direct sequencing. The association between EMT, p53 mutation status, and statin use as well as the patients’ clinical information was statistically analyzed. Correlations were compared using Pearson's chi-square test and overall survival were compared using the log-rank test.

      Result:
      When mutant p53 (R175H, R273H) were transfected, H1650 cells showed EMT like morphological changes. E-cadherin expression was decreased and vimentin expression was increased in H1650 harboring mutant p53 (H1650[mut.p53]). Additionally, H1650[mut.p53] obtained more aggressive invasiveness compared to H1650 harboring wild type p53. However, simvastatin-treated H1650[mut.p53] lost EMT character changes and aggressive invasiveness. According to the medical records, about 20% of the patients took statins (simvastatin, pravastatin, and so on) as a treatment of hyperlipidemia or coronary artery disease. Consistent with the results of in vitro experiments, IHC showed that statin administration was correlated to fewer EMT only in the patients with mutant p53. Moreover, the statin-administrated group showed significantly better survival compared to the non-statin group (p=0.04), which was observed only in the patients with mutant p53.

      Conclusion:
      Statins suppressed EMT and improved the prognosis of patients with lung adenocarcinoma in a p53 mutation-dependent manner.