Virtual Library

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    E05 - Management of Pleural Effusion (Multiple Cases) (ID 5)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 8
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      Case One Part Two (ID 5665)

      14:00 - 15:30  |  Author(s): T. Saghaie

      • Abstract
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      Abstract not provided

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      Case Two Part One (ID 5666)

      14:00 - 15:30  |  Author(s): T. Saghaie

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      Abstract not provided

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      Case Two Part Two (ID 5667)

      14:00 - 15:30  |  Author(s): T. Saghaie

      • Abstract
      • Presentation
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      Abstract not provided

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      E05.1 - Case One Part One (ID 392)

      14:00 - 15:30  |  Author(s): T. Saghaie

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      Abstract not provided

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      E05.2 - First Presentation with Large Effusion - Diagnostic / Treatment Pathway (ID 393)

      14:00 - 15:30  |  Author(s): M. Phillips

      • Abstract
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      Abstract not provided

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      E05.3 - What Procedure - VATS / Medical Pleuroscopy in a Fit Patient (ID 394)

      14:00 - 15:30  |  Author(s): P. Lee

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      Abstract not provided

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      E05.4 - Small Tube vs Large Tube - Choice of Sclerosant (ID 395)

      14:00 - 15:30  |  Author(s): K.Y. Yoneda

      • Abstract
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      Abstract not provided

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      E05.5 - Trapped Lung - What Do We Do (ID 396)

      14:00 - 15:30  |  Author(s): P.A. Ugalde

      • Abstract
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      Abstract not provided

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    E13 - High Risk Patients and Low Risk Surgeons (ID 13)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Surgery
    • Presentations: 4
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      E13.1 - Salvage Surgery After Radiation: Residual Tumour and Complications (ID 432)

      14:00 - 15:30  |  Author(s): C. Dickhoff, M.A. Paul, J.J. Kloek

      • Abstract
      • Presentation
      • Slides

      Abstract
      Salvage surgery after Radiation: Residual Tumor and Complications Definitive chemoradiotherapy is increasingly used in the treatment of patients with stage III non-small-cell lung cancer. Historically, local control and overall survival rates have been poor. To improve local control higher doses of radiotherapy are being investigated, with or without new chemotherapeutic agents. Dose-escalation appears to provide a modest benefit in terms of preventing local failure and improving overall survival, but the benefit comes at a price: The risk of both early and late toxicity appears to increase as well. Despite improved treatment remnants of vital tumor often persist. In many patients this has no clinical significance because prognosis is determined by the occurrence of distant metastases. However, some tumors do not metastasize and local recurrence becomes a problem. These patients are then referred for possible surgical resection. Because of this possibility of isolated local recurrence, doctors Increasingly perform early re-staging procedures after definitive chemoradiotherapy. In case of persistent tumor patients are referred for resection as “late-induction cases”. Another category consists of patients presenting with complications caused by high-dose irradiation. These late sequalae of radiotherapy are: bronchial stenosis, fatal haemoptysis, esophageal stenosis, fistula’s, cardiac complications and the occurrence of 2nd primary tumors. They may occur as early as 3 months, but an interval of one or more years is not uncommon (1) Some of these complications, such as fistula’s or bronchial stenosis , require urgent surgical correction, due to their severe symptoms. Late surgical resection in irradiated patients has been described with good success (2). However, the impaired wound healing capacity of irradiated tissue makes surgery hazardous and the liberal use of non-irradiated tissue flaps is recommended. We describe our experience of surgical correction of late complications after concurrent chemoradiotherapy: Fistulae: A tracheo-esophageal fistula or broncho-esophageal fistula is best treated by esophageal resection and tube-stomach replacement, because the esophagus is often stenotic and mere interposition of a muscle flap between airway and esophagus will not suffice. Stenosis: Bronchial stenosis requires resection, but re-anastomosis carries a high risk of dehiscence. We have seen two cases of dehiscence after 6 and 8 weeks, after the sutures had been absorbed, in spite of wrapping the suture line with an intercostal muscle flap. Tracheomalacia requiring temporary stenting has also occurred following partial tracheal resection. Hemoptysis: Necrosis and cavitation of an irradiated area may be complicated by a fungal infection (aspergillus), causing haemoptysis. These patients, who are often weak and malnourished, are treated by a staged procedure: First thoracic wall fenestration for adequate drainage of the infectied area together with insertion of a gastrostomy or jejunostomy catheter for nutritional support. We try to avoid nasogastric tubes in these patients, to avoid aspiration. At a second stage the cavity is filled with a pedicled muscle flap. Depending on the size and location of the cavity, a partial thoracoplasty is also performed. The interval between the two operations should be limited if the cavity extends towards the hilum, because erosion of a vessel wall may cause fatal hemorrhage. New treatments for lung cancer create new situations for the thoracic surgeon. Good skill, knowledge of old techniques such as thoracoplasty and the use of muscle flaps, and emphasis on nutritional support are mandatory to solve these problems.

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      E13.2 - Standards and Benchmarking of Surgery (ID 433)

      14:00 - 15:30  |  Author(s): A. Brunelli

      • Abstract
      • Presentation
      • Slides

      Abstract
      Managed care system, public accountability, cost containment, pay-for-performance and ranking culture demand Quality of care to be monitored through appropriate instruments. Outcome endpoints (i.e. morbidity and mortality) are still the most widely used quality indicators in thoracic surgery. Outcomes however should be reported in the most correct way to prevent risk-averse behaviours and misleading information. They need risk-adjustment, as different case-mixes at different institutions may influence outcome and those units operating on older and sicker patients would be penalized without an appropriate risk-adjustment. Therefore, risk-modelling must become the logical and necessary approach for provider profiling and comparative audit. The most important tool of any quality assessment endeavour is a database that is made up of a representative sample of the study group of interest. The gold standard for data should be a specialty-specific, procedure-specific, prospectively maintained, periodically audited, electronic database that contain, at the minimum, a core set of variables that has been demonstrated to be associated with outcome. The practical steps that should be planned and possibly recorded to construct a solid clinical database are a clear definition of the data sources and the creation of a list of variables (and their definitions) that will constitute the database. These steps will permit that 1) the database can be used even by subjects that did not participate to its construction, 2) the database can be audited by external data managers to assess quality of data, 3) changes in data collection or variables recording may be adequately planned. The importance of the source and the quality of data cannot be overemphasized enough. Most of the data that are of clinical interest derive from clinical records or other attached documents, such as laboratory exams or PFTs. One of the most critical aspects of the database construction is the extraction of the data from the medical record to the database. Wherever possible, data should be entered in real time, at the point of capture; to this end a networked database should be accessible in the operating theatre, the ward, the clinic and the multidisciplinary team meeting room. When possible this data should be used to generate documents such as operation notes, MDT report, correspondence, so that data capture becomes integral to routine patient care. The person in charge of capturing or transferring data into a database should be properly qualified and adequately trained. A Clinical Audit Lead should be selected within each unit who will be responsible for the accuracy and quality of data collection. The data should be periodically checked for discrepancies, inconsistencies, missing values, in order to ensure a high quality database. In fact no model or predictive equation can be better than the data upon which it is based. If any underperformance in data collection would be detected this should be reported to all persons involved in the process of data recording with the final objective of continuously improving the quality of the database. The European Society of Thoracic Surgeons (ESTS) appointed a Database Committee responsible to develop and maintain an online clinical Database with the aim to collect clinical data from thoracic surgery units across Europe. The ESTS Database is an online database, which is free to members and directly accessible from the link on the ESTS homepage. The main purpose of the ESTS database is for quality monitoring and improving activities. Several outcome and process indicators are included in the dataset. These indicators have been used to construct a Composite Performance Score, which is used as one of the parameters necessary for the European Institutional Accreditation System (EIAS). The EIAS is a process aimed at standardization of thoracic surgery practice across European units. It is currently based on the information submitted to the ESTS Database and focused on major lung resections for lung cancer, the prevalent activity in our specialty. In the construction of the CPS, indicators covering all three temporal domains of our practice (preoperative, intraoperative and postoperative) were selected. These indicators included risk-adjusted hospital mortality and morbidity (outcomes) and 3 process measures derived from published guidelines: the proportion of lung resection candidates with measured DLCO, the proportion of candidates to lung resection for NSCLC with clinically suspicious nodal disease submitted to preoperative invasive mediastinal staging and the proportion of patients with a intraoperative mediastinal staging according to the ESTS published guidelines. The final composite score combined 3 processes and 2 outcomes indicators into a single comprehensive quality score which was able to discriminate between the units entering in the comparison process. Units eligible for the accreditation process are then inspected by a team of auditors appointed by the ESTS to verify a sample of data submitted to the ESTS database and the structural, procedural and qualification characteristics of the unit and surgeons working in that unit. Most recently the ESTS Executive Committee revised the structural characteristics of general thoracic surgery unit in Europe with the aim to provide a comprehensive document in line with the quality initiatives of the Society and serving as a guide for harmonizing the general thoracic surgical practice in Europe. That document will be used as a reference for future quality initiatives and educational activities of the society

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      E13.3 - Micrometastases: Magic or Mainstream? (ID 434)

      14:00 - 15:30  |  Author(s): Y. Wu

      • Abstract
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      Abstract not provided

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      E13.4 - Decision-Making and the New IASLC Staging System (ID 435)

      14:00 - 15:30  |  Author(s): P. Goldstraw

      • Abstract
      • Presentation
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      Abstract
      The 7th edition of TNM for Lung Cancer, introduced in January 2010, was based entirely upon recommendations from the IASLC Staging and Prognostic Factors Committee. The enormous size of the data base, its international accrual of cases diagnosed over a relatively short time period and its inclusion of cases treated by all modalities of care, coupled with detailed analysis and intensive validation ensured that this version aligned stage with prognosis more accurately than ever before. This was achieved by introducing new size cut-points for tumour size, re-assigning some T and M descriptors and moving some T, N, and M combinations to new stage groupings. Inevitably there are questions as to whether there should be consequent changes to established treatment algorithms. These discussions will focus upon the following scenarios: a) Larger node negative tumours, > 5cms, are now included in stage II. In the past 10 years we have seen data showing that stage II cases benefit from adjuvant chemotherapy after complete resection. Do these "new" stage II cases benefit from adjuvant therapy? b) Cases in which there are additional tumour nodules in the tumour-bearing lobe and other ipsilateral lobes have with certain combinations of N category, been down-staged to IIIA. Selected cases of stage IIIA disease have benefitted from resection, usually in a multi-modality setting. Should these cases, now included in stage IIIA be treated with regimens including surgery? c) Tumours invading certain mediastinal structures that were classified as T4 in previous editions of TNM have not been re-assigned but when associated with N0 or N1 disease these cases have been down-staged to stage IIIA. Should they also be considered for surgery in a multi-modality setting? Whilst it is impossible to give dogmatic and unequivocal advice on the right answer to these questions the speaker hopes to give some insights into the factors which might influence the decisions made by the Multi-Disciplinary Team in such situations. Other issues raised by the 7th edition include: a) The distinction between pulmonary metastases and synchronous primary tumours has been clarified and the opinion of the pathologist has been emphasised in this distinction. Thus in cases in which there is more than one malignant nodule biopsy of additional lesions may be required if such a distinction would alter the treatment advised in any case. b) The IASLC nodal map and definitions of nodal stations and zones are now the recommended means of describing regional lymph node involvement in lung cancer. All members of the MDT should be familiar with this nomenclature. c) The definition of an R0 resection now requires that a defined minimum of lymph nodes/stations be removed by the surgeon and examined by the pathologist. Surgeons and pathologists need to comply with this requirement and other members of the MDT need to understand this expanded definition. d) The 7th edition of TNM and the new IASLC/ATS/ERS classification of Adenocarcinomas may influence the management of screen-detected lesions. The new T category of T1a tumours no larger than 2cms and the fall in prognosis seen in lesions above this threshold may influence the choice of approach to lesions around this watershed, one's policy of structured surveillance and the extent of surgical resection for lesions confirmed to be malignant. As LDCT screening becomes more widely available the MDT managing these cases will need to consider these matters when developing their investigative algorithms.

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    GR01 - Surgery and the New Stage IIIA (ID 16)

    • Event: WCLC 2013
    • Type: Grand Round Session
    • Track: Surgery
    • Presentations: 4
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      GR01.1 - Surgery for N2 Disease: Where To and When To Now? (ID 446)

      14:00 - 15:30  |  Author(s): M. Tsuboi

      • Abstract
      • Presentation
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      Abstract not provided

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      GR01.2 - Where Does T3 Eend and T4 Begin? (ID 447)

      14:00 - 15:30  |  Author(s): V. Rusch

      • Abstract
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      Abstract not provided

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      GR01.3 - Role of Neoadjuvant and Adjuvant Therapies (ID 448)

      14:00 - 15:30  |  Author(s): S. Watanabe

      • Abstract
      • Presentation
      • Slides

      Abstract
      1. Introduction Lung cancer has remained to be the leading cause of cancer-related death in many countries. Most patients are diagnosed at an advanced stage, stage III or IV. A way to improve surgical outcome would be the administration of chemotherapy before or after the surgical procedure. 2. Neoadjuvant therapy The preoperative induction therapy offers several benefits: (1) an increased percentage of patients completing the planned dose of chemotherapy, (2) the probability to treat micrometastatic tumor dissemination preoperatively, (3) the ability to assess response to the chemotherapy as a prognostic indicator, and (4) the probability to increase resectability by the tumor regression. 2.1. Induction chemotherapy Numbers of phase II trial using induction chemotherapy can be found in the previous literatures. Phase III neoadjuvant trial results including stage IIIA disease are summarized in Table1. Two studies reported by Roth (1994) and Rosell (1994) suggested that induction therapy followed by surgery could lead to improved outcomes, however, recent large scale studies did not show the improvement of survival in stage IIIA patients received neoadjuvant chemotherapy.  2.2. Induction chemotherapy with third-generation agents Results of previous studies, all of them are phase II study, evaluating the efficacy of induction chemotherapy with third-generation agents are shown in the table 2. These trials showed the feasibility and potential benefit of induction chemotherapy with combination or cisplatin and third-generation agents for stage III patients. Since the data of phase III trial with large sample size are lacking, the adequate regimen of induction chemotherapy has yet to be defined. 2.3. Induction chemotherapy or induction chemoradiotherapy? Whether induction radiotherapy adds benefit when surgery is planned is an important clinical question, because the addition of each modality increase the possibility of morbidity and mortality of treatment. To investigate the benefit of neoadjuvant radiation therapy, Shah (2012) conducted systematic review and meta-analysis. None of the studies demonstrated a survival benefit to adding induction radiotherapy to induction chemotherapy versus induction chemotherapy alone. The meta-analysis performed on randomized studies demonstrated no benefit in survival from adding radiation (HR: 0.93; p=0.81), nor did the meta-analysis performed on retrospective studies (HR: 0.77; p=0.24). The most promising use of induction chemoradiotherapy is to treat the superior sulcus tumor (SST) where preoperative local tumor regression is a key to achieving complete resection. Rush (2007) reported the results of SWOG 9416 (Intergroup 0160) phase II trial, which tested the feasibility of induction chemoradiotherapy for SST, on the basis of improved outcomes in other subsets of stage III NSCLC. Pathologic complete response (CR) or minimal microscopic disease was seen in 61 (56%) resection specimens. Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Kunitoh (2008) reported the similar results of Japan Clinical Oncology Group (JCOG) phase II trial (JCOG 9806), which was conducted for testing the feasibility of induction chemoradiotherapy for NSCLC-SST patients. There were 12 patients with pathologic CR. The disease-free and overall survival rates at 3 years were 49% and 61%, respectively; at 5 years, they were 45% and 56%, respectively. They concluded that the trimodality approach was safe and effective for the treatment of patients with SST 3. Adjuvant therapy 3.1. Adjuvant chemotherapy The NSCLC Collaborative Group (1995) reported a meta-analysis of 14 clinical trials addressing the role of adjuvant chemotherapy for resected NSCLC. There was no statistically significant survival benefit in group of patients received adjuvant chemotherapy, but a trend toward better survival prompted further studies. Subsequently, the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis based on individual patient data collected from the 5 largest trials (4,584 patients) of cisplatin-based adjuvant chemotherapy in completely resected patients with NSCLC was performed. This analysis also showed a significant survival benefit with adjuvant chemotherapy, with an overall hazard ratio (HR) of 0.89, translating into a 5-year absolute survival benefit of 5.4%. Then in 2010, the NSCLC Meta-analyses Collaborative Group reported a meta-analysis of 34 clinical trials with 8,447 patients (3,323 deaths) addressing the benefit of adjuvant chemotherapy for resected NSCLC. Among those, the overall hazard ratio to survival in patients received cisplatinum-based adjuvant chemotherapy by stage suggests absolute improvements in 5-year survival of 5% for stage III disease (from 30% to 35%). 3.2. Adjuvant radiotherapy In 1988, postoprative radiotherapy (PORT) Meta-analysis Trialists Group collected individual data on 2,128 patients from nine available randomized trials of PORT versus surgery alone. They reported a 21% relative increase in the risk of death, which was equivalent to an absolute detriment of 7% at 2 years, with PORT reducing overall survival from 55% to 48% after resection. Subgroup analysis suggested that the adverse effect on overall survival was most notable for patients with stage I/II (N0-N1) tumors, whereas there was no clear evidence of either adverse effect or benefit for stage III disease. The results of the PORT meta-analysis, however, are probably not applicable to current therapy because of recent major improvements in radiation treatment planning and delivery. 4. Neoadjuvant or adjuvant chemotherapy? Which is the better treatment, induction or adjuvant chemotherapy? Some concern has also arisen regarding adjuvant chemotherapy compliance, with most trials using cisplatin doublets reporting delivery of only 60% of planned treatment. Induction chemotherapy seems better tolerated, more than 80% of the patients received the full planned treatment at the difference of adjuvant chemotherapy. In the LACE meta-analysis, 33% of patients in the chemotherapy arm did not start or finish the planned chemotherapy regimen, reflecting the difficulty of adjuvant chemotherapy administering such taxing therapies to a postoperative population. 6. Conclusions Although definitive chemoradiation remains a standard of care for stage IIIA NSCLC, alternative approaches such as induction chemotherapy and surgery for a selective group of patients can be considered. When surgical resection after induction therapy can be performed with low risk and a good chance of complete resection, it might provide an optimal outcome. The decision to proceed with resection after induction therapy must include a detailed preoperative pulmonary function evaluation as well as a critical intraoperative assessment of the feasibility of complete resection. Figure 1Figure 2

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      GR01.4 - Multiple Primaries, Satellites or Intrapulmonary Metastases? (ID 449)

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

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      Abstract not provided

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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 14
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      MO06.01 - Clinical features of patients with non small cell lung cancer who harbor EGFR mutation and present with miliary intrapulmonary or disseminated carcinomatosis (ID 1744)

      16:15 - 17:45  |  Author(s): H.J. Kim, S.H. Kang, S.J. Kim, G.H. Yoo, K.Y. Lee

      • Abstract
      • Presentation
      • Slides

      Background
      It is reported that epidermal growth factor receptor (EGFR) mutation is frequent in non-small cell lung cancer (NSCLC) patients who are presenting with miliary intrapulmonary carcinomatosis. We often encountered disseminated carcinomatosis as well as intrapulmonary carcinomatosis. This study aims to investigate the clinical characteristics of patients with miliary intrapulmonary or disseminated carcinomatosis.

      Methods
      Patients with advanced NSCLC who harbor EGFR mutation and presented with miliary intrapulmonary or disseminated carcinomatosis were enrolled respectively, from September 2005 to January 2011. EGFR mutations in exons 18-21 were confirmed by pyroseqeuncing method after genomic DNA was extracted from paraffin-embedded tissue specimens. Clinical characteristics, responses to treatment and outcome were collected from medical records.

      Results
      Histology of sixty-four patients with NSCLC who have EGFR mutation revealed adenocarcinoma. The most frequent mutation was in-frame deletions in exon 19 (n=44, 68.7%). An arginine-for-leucine substitution at amino acid 858 (L858R) and point mutation in exon 18 (G719A) were detected in 19 (29.7%) and 1 (1.7%) patient, respectively. Patients with miliary intrapulmonary or disseminated carcinomatosis were more common in female (80.0% vs. 55.1%, p=0.084), non smoker (80.0% vs. 53.1%, p=0.063), and in-frame deletions at exon 19 (86.7% vs. 63.3%, p=0.087), however there were no significant difference statistically. They showed relatively shorter progression free survival (PFS) to EGFR tyrosine kinase inhibitors (median PFS 9.7 vs, 12.8 months, p=0.003) and poorer overall survival (median OS 15.9 vs. 29.0 months, p=0.077) compared to patients without miliary metastasis. In multivariate analysis, higher metabolic tumor volume (MTV) in PET-CT was confirmed to be an independent predictor of shorter overall survival, when considered together with tumor stage, gender and smoking status (hazard ratio for MTV: 1.001; p = 0.027).

      Conclusion
      The data indicate that NSCLC presenting miliary intrapulmonary or disseminated carcinomatosis were more common in female, adenocarcinoma, non smoker and in-frame deletions in exon 19 was comparatively frequently detected in those patients, however there were no statistically significant difference. PFS to EGFR tyrosine kinase inhibitors was less in patients with miliary intrapulmonary or disseminated carcinomatosis and overall survival was poorer compared to patients without miliary metastasis. Poor clinical course of these patients might be associated with high tumor burden represented by metabolic tumor volume or total lesion glycolysis.

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      MO06.02 - Monitoring EGFR T790M with plasma DNA in lung cancer patients treated with EGFR tyrosine kinase inhibitor in prospective observational study (ID 1399)

      16:15 - 17:45  |  Author(s): K. Aoe, N. Sueoka-Aragane, N. Katakami, M. Satouchi, S. Yokota, K. Iwanaga, S. Kimura, S. Negoro

      • Abstract
      • Presentation
      • Slides

      Background
      Detection of mutations with plasma DNA isolated from peripheral blood is an alternative method of biopsy. The gatekeeper T790M mutation of EGFR has been observed in half of patients who acquired resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI). Considering that majority of lung cancer recurrence occurs as distant metastases, determination of T790M using a non-invasive mutation detection system with plasma DNA would be useful. We recently developed a novel non-invasive, fully-automated monitoring system, MBP-QP (mutation-biased PCR and quenching probe) method, to detect T790M using plasma DNA. The detection limit was two copies of control plasmid and 0.2 ng of genomic DNA, the T790M mutation was detected in plasma DNA from 53% of lung adenocarcinoma patients who acquired resistance in the previous retrospective study. Compared with the other methods such as PNA-LNA PCR clamp, the cycleave PCR technique, and digital PCR, the MBP-QP method is simple, sensitive, and reflective of clinical course. To determine the usefulness of the MBP-QP method for monitoring T790M during treatment of EGFR-TKI, a prospective clinical study has been performed.

      Methods
      This is a prospective, multicenter observational study involving lung adenocarcinoma patients carrying EGFR activating mutations such as L858R and exon 19 deletions treated with EGFR-TKI. Primary objective was to determine whether T790M was detected with plasma DNA at the time point of progressive disease (PD), and the secondary objective was correspondence of T790M with plasma and cancer specimens. The association between detection of T790M and effect of EGFR-TKI were also investigated as the exploratory objective. Plasma DNA was isolated from the patients before treatment of EGFR-TKI, every four months during treatment, at the time of occurrence of PD, and after two courses of post-chemotherapy.

      Results
      Ninety lung adenocarcinoma patients treated with EGFR-TKI were enrolled, in whom 51% of L858R and 49% of exon 19 deletions were determined in tumor specimens before treatment. Most of the patients, 92.1%, had adenocarcinoma. 62% (55/90) was stage IV, and 29% (26/90) had postoperative recurrent disease. 43% (38/90) of the patients were treated with EGFR-TKI as the first-line therapy, and the rest of them were previously treated including 17% of the patients experienced with EGFR-TKI. T790M was detected in 23% (21/90) among the entire patients. Forty patients showed PD two years after beginning of this trial, and T790M was detected in 13 patients among the patients who acquired resistance to EGFR-TKI; the frquency of T790M positive among the patients with PD was 32.5% (13/40). Although T790M was temporarily detected during treatment of EGFR-TKI in 8 patients who were still responded to EGFR-TKI, is disappeared after that.

      Conclusion
      T790M was detected in plasma DNA isolated from lung cancer patients whose diseases were progressed. Continuous detection of T790M in plasma DNA seemed to be related with occurrence of PD.

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      MO06.03 - Bevacizumab and erlotinib or bevacizumab, cisplatin and pemetrexed in patients with metastatic non-small cell lung cancer: EGFR mutation based treatment allocation and repeat biopsy at progression in the SAKK19/09 (BIOPRO) trial (ID 1862)

      16:15 - 17:45  |  Author(s): O. Gautschi, N. Mach, L. Bubendorf, Q. Li, A. Zippelius, R. Stahel, R. Cathomas, M. Fruh, D. Betticher, S. Peters, D. Rauch, M. Brutsche, S. Savic, R. Jaggi, S. Rothschild, E. Oppliger Leibundgut, C. Pilop, L. Stalder, M. Pless, A. Ochsenbein

      • Abstract
      • Presentation
      • Slides

      Background
      Treatment allocation by EGFR mutation and maintenance therapy are two new standards for patients (pts) with metastatic non-small cell lung cancer (NSCLC). This multicenter phase II trial (NCT01116219) for the first time prospectively tested pemetrexed and bevacizumab maintenance therapy in pts with EGFR wild type NSCLC, and included repeat biopsy at progression to study molecular mechanisms of drug resistance. Pts with EGFR mutation were treated with erlotinib and bevacizumab, based on the results of the previous SAKK19/05 trial.

      Methods
      100 pts were enrolled with metastatic nonsquamous NSCLC, sufficient material for mutation analysis and translational research, and consent to repeat biopsy at progression. Pts with EGFR wild type received 4 cycles of bevacizumab 7.5mg/kg, cisplatin 75mg/m2 (or carboplatin AUC5) and pemetrexed 500mg/m2 every 3 weeks, followed by maintenance therapy with bevacizumab and pemetrexed until progression. Pts with EGFR mutation received bevacizumab 7.5 mg/kg every 3 weeks and erlotinib 150 mg daily until progression. Pts were followed by CT-scan every 6 weeks and repeat biopsy was performed at progression. The primary endpoint was progression free survival (PFS) at 6 months. For an unpromising PFS at 6 months rate of ≤20% and a promising rate of ≥35%, 77 patients with EGFR wild type were needed to reach a power of 90% and an alpha level of 5%. Secondary endpoints were median PFS, overall survival (OS), best response rate of CR+PR (RECIST), and further biomarkers including KRAS, thymidylate synthase (TS), and multigene expression.

      Results
      Seventy-seven pts with EGFR wild type and 20 pts with EGFR mutation were evaluable, 3 pts were not evaluable. Pts on bevacizumab and chemotherapy received on average 9 cycles (range 1-25). No unexpected toxicities were observed. PFS at 6 months was 45.5% (CI: 34.1%, 57.2%), median PFS was 6.9 (CI: 4.6, 8.3) months, OS was 12.1 (CI: 8.7, 14.7) months, and best response rate of CR+PR was 62%. Sixteen pts remain on treatment. Repeat biopsy at progression was successful in 31 of 39 (79%) of patients on trial treatment, and except for one transient pneumothorax, no relevant complications occurred. KRAS mutation was associated with poor overall survival (HR 2.0, CI: 1.05, 3.88; P=0.03), but not with PFS or best response. Pts on bevacizumab and erlotinib received on average 16 cycles (range 6-37). PFS at 6 months was 70.0% (CI: 45.7%, 88.1%), median PFS was 14.0 (CI: 8.8, NA) months, median OS is not yet reached, best response rate of CR+PR was 70%, 11 pts remain on treatment. Further analysis of serial serum and tumor samples is ongoing.

      Conclusion
      Compared with the previous POINTBREAK trial of pemetrexed and bevacizumab maintenance in genetically unselected pts, this trial demonstrates almost identical survival rates in pts with EGFR wild type. KRAS mutation was prognostic, repeat biopsy at progression was feasible, and laboratory analysis is ongoing to validate TS and to develop a predictive gene signature. Firstline therapy with erlotinib and bevacizumab is promising in pts with EGFR mutation, and this combination is further tested in the ongoing ETOP 2-11 BELIEF trial.

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      MO06.04 - A Randomized Phase 3 Study Comparing First-line Pemetrexed plus Cisplatin Followed by Gefitinib as Maintenance with Gefitinib Monotherapy in East Asian Patients with Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer (nSqNSCLC) (ID 1943)

      16:15 - 17:45  |  Author(s): J.C. Yang, K. Park, T.S.K. Mok, J.H. Kang, V. Srimuninnimit, C. Lin, D. Kim, C. Tsai, H. Barraclough, S. Altug, M. Orlando

      • Abstract
      • Presentation
      • Slides

      Background
      The IPASS study reported that in a clinically selected lung cancer patient population (East Asian, light ex-/nonsmokers with adenocarcinoma) gefitinib (G) provided superior progression-free survival (PFS) than chemotherapy with carboplatin/paclitaxel; however, the benefit was restricted to patients with epidermal growth factor receptor gene (EGFR)-mutant tumors whereas patients with wild-type (WT) tumors had inferior outcomes. Pemetrexed, in combination with cisplatin, (PC) has demonstrated improved efficacy in first-line treatment of nSqNSCLC and is a preferred chemotherapy choice. The primary objective was to compare PC induction therapy followed by G as maintenance therapy to G monotherapy, in terms of PFS, as first-line treatment in a similar “IPASS” patient population.

      Methods
      Patients with unknown EGFR mutation status (N=236) were randomized 1:1 to PCG treatment for 6 cycles or G. Patients on Arm A without progressive disease after 6 cycles received G maintenance therapy. Stage IIIB/IV nSQ NSCLC, light ex-smokers or never-smokers, and ECOG PS 0-1 patients with no prior systemic therapy were eligible. Primary endpoint analysis was conducted using a Wilcoxon test after 169 PFS events. This assessment provided 80% power if the true hazard ratio (HR) was 0.65. Tissue samples from consenting patients were analyzed for EGFR mutation status.

      Results
      Baseline characteristics were balanced across treatment arms. One-hundred-forty-one patients provided tissue for EGFR mutation analysis (59.7%). Mutation status was determined for 74 samples (52.5%);50/74 samples (67.6%) had mutations (mutation type: EX19_DEL, n=25; L858R, n=23; other, n=2). The primary analysis of PFS showed no significant difference between treatment arms (Wilcoxon p=0.217). The unadjusted HR was 0.85 (95% CI: 0.63, 1.13). During most of the study period, the KM curve for PC remained above the G curve. In a prespecified subgroup analysis, EGFR-by-treatment interaction was statistically significant (p=0.008), showing treatment effect significantly differed by EGFR mutation status. The HR for PFS favored PC in both EGFR-mutated and EGFR-WT patients, but the magnitude of benefit was greater in EGFR-WT patients [EGFR-mutated patients HR=0.83 ([95% CI: 0.42, 1.62], p=0.585); EGFR-WT HR 0.18 ([95% CI: 0.06, 0.51], p=0.001)]. HRs for ITT and EGFR-mutated patients should be interpreted with caution as they were not constant. Arm A had more patients with ≥1 possibly drug-related CTCAE grade 3/4 TEAEs but similar rates of all-grade TEAEs during induction. Selected grade 3/4 or all-grade TEAEs which occurred significantly more included anemia, neutropenia, emesis, and neuropathy in Arm A and AST/ALT elevations, diarrhea, pruritus, and skin rash in Arm B. The toxicity profile was similar in both arms during the G maintenance period.

      Conclusion
      In the ITT population, the PFS difference was not statistically significant. In the biomarker assessable population, results are consistent with the existing consensus that patients with WT EGFR do not benefit with front-line EGFR TKI treatment. Overall, the results show that identification of the EGFR mutational status is key in the management of advanced NSCLC. Even in the presence of clinically favorable predictors of EGFR mutation positivity (>60% in our population), “empirical” choice of EGFR TKIs as front-line therapy may be detrimental to NSCLC patients without EGFR mutations.

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      MO06.05 - DISCUSSANT (ID 3937)

      16:15 - 17:45  |  Author(s): P.L. Mitchell

      • Abstract
      • Presentation
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      Abstract not provided

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      MO06.06 - Oral vinorelbine (NVBo) and cisplatin (P) or pemetrexed (Pem) and P as first-line chemotherapy for non squamous (NS) metastatic or locally advanced non small cell lung cancer (M or LA NSCLC): Final results of a prospective randomised phase II trial (NAVoTrial 1) (ID 276)

      16:15 - 17:45  |  Author(s): E. Tan, M. Krzakowski, J. Kollmeier, R. Gervais, E. Dansin, M. Serke, A. Favaretto, L. Havel, M. Cobo, A. Szczesna, L. Ciuffreda, J. Jassem, M. Nicolini, R. Ramlau, D. Amoroso, B. Melotti, M.T. Almodovar, N. Vaissière, M. Riggi, J. Bennouna

      • Abstract
      • Presentation
      • Slides

      Background
      NVBo and P are an established regimen in advanced NSCLC. The approval of Pem and P in NS NSCLC recognises histology as treatment driver even if the higher chemosensitivity of NS NSCLC is recognised and reported with other chemotherapies (Ardizzoni. JNCI 2007). NVBo + P also showed better survival in NS NSCLC than in Squamous NSCLC (Tan. Ann.Oncol. 2009). The current randomised (2:1) phase II trial assessed disease control (DCR) (SD + PR + CR) of NVBo/CDDP or PEM/CDDP in NS NSCLC.

      Methods
      Stage IIIB/IV untreated/relapsed NS NSCLC pts were randomised to receive q3w NVBo 80 mg/m² D1D8 (60 at Cycle 1) + P 80 mg/m² D1 (Arm A) or Pem 500 mg/m² + P 75 mg/m² D1 (Arm B). After 4 cycles of combination, non PD pts received single agent NVBo (Arm A) or PEM (Arm B) as maintenance until progression or toxicity. Pts were randomised on a 2/1 basis and stratified according to Stage (IIIB - IV - relapse), non SCC confirmed by histology or cytology, gender, smoking status and centre.

      Results
      From 11/09 to 02/11, 153 patients were enrolled in 31 centers and randomised to Arm A (102 pts) or Arm B (51 pts). DCR after combination and maintenance was 75.0% (95% CI, 65.3 to 83.1) in Arm A and 76.5% (95% CI, 62.5 to 87.2) in Arm B. Median PFS was 4.2 (95% CI, 3.6 to 4.7) and 4.3 months (95% CI, 3.8 to 5.6) in Arm A and Arm B, respectively. Median OS was 10.2 months (95% CI, 7.8 to 11.9) and 10.8 months (95% CI, 7.0 to16.4) in Arm A and Arm B, respectively. During the combination period Grade 3/4 neutropenia was 44.0% in Arm A and 18.3% in Arm B but febrile neutropenia was 2% in both arms; grade 3/4 thrombopenia was 0% and 6% in Arm A and Arm B, respectively.

      Conclusion
      Both doublets reported good efficacy and acceptable tolerability. The maintenance allowed continuation of effective treatment with either oral vinorelbine or pemetrexed as single agent, with an acceptable safety with both agents. These results are sufficiently compelling to consider whether a phase III randomised non inferiority study with oral vinorelbine maintenance after induction vinorelbine/cddp could be as effective as pemetrexed maintenance. An oral maintenance may be a definite advantage over intravenous maintenance.

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      MO06.07 - Daily administration of oral vinorelbine: data from a phase I trial in patients with advanced Non-Small Cell Lung Cancer (NSCLC) (ID 2395)

      16:15 - 17:45  |  Author(s): A. Tufman, A. Borgmeier, S. Guetz, J. Von Pawel, A. Rittmeyer, R.M. Huber

      • Abstract
      • Presentation
      • Slides

      Background
      Metronomic regimens, in which small, frequent doses of chemotherapy are administered, have been suggested to lower treatment-associated toxicities while maintaining, or even improving, efficacy. The high frequency of administration aims to expose tumour cells continuously to the drug, preventing recovery between cycles and possibly improving tumour control. We present the clinical and pharmacokinetic data of a phase I dose finding study in which the maximum tolerated dose (MTD) of daily oral vinorelbine was determined in pretreated patients with advanced NSCLC.

      Methods
      Patients (pts) were treated daily with oral vinorelbine (Navelbine® Oral) at fixed doses of 20 mg/d, 30 mg/d, 40 mg/d or 50 mg/d for 21 days of each four-week cycle. Blood sampling for pharmacokinetic assessment was carried out in the first cycle just before drug intake (trough concentrations) on days 1, 8, 15 and 21 and additionally at 1 h, 3 h and 24 h after drug intake on days 1 and 21.

      Results
      Daily administration of oral vinorelbine was well tolerated up to 30 mg/d without any dose limiting toxicities (DLT). At 40 mg one of three patients experienced DLT in cycle 1 and another patient in cycle 2. The MTD was reached at 50 mg/d when three out of six pts experienced DLT in cycle one. The reported DLTs included febrile and non-febrile neutropenia (6 DLTs) as well as fatigue (1 DLT). One patient had an exceptionally good clinical response with a long-lasting tumour remission. Twenty-one pts were evaluable for pharmacokinetic analysis. Blood concentrations of vinorelbine increased with escalating dose levels. Pts were continuously exposed to the drug over the 21-day treatment period as indicated by measurable trough concentrations on days 8, 15 and 21. A slight accumulation of vinorelbine was observed until day 8 based on residual concentrations (ratio c~24h ~ranged 1.96-2.03 between day 1 and either day 8, 15 or 21). The accumulation had no impact on global exposure at repeated dosing, as only minor differences in blood concentrations were detected between day 1 and day 21 (ratio d21/d1 median AUC~0h-24h~: 0.81, 0.92, 1.07, 0.56 at 20 mg/d, 30 mg/d, 40 mg/d and 50 mg/d, respectively). Data on four pts experiencing DLT were available (1 pt at 40 mg/d, 3 pts at 50 mg/d). Only one DLT correlated with an evidently high 24 h blood exposure to vinorelbine.

      Conclusion
      The recommended dose for daily administration of oral vinorelbine is 30 mg in cycle 1 followed by 40 mg in subsequent cycles in the absence of DLT. Further studies are necessary to determine the clinical impact, and possible anti-angiogenic profile of the daily administration schedule of vinorelbine.

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      MO06.08 - A phase 2 randomized open-label study of ramucirumab (IMC 1121B; RAM) in combination with first-line platinum-based chemotherapy in patients (pts) with recurrent or advanced non-small cell lung cancer (NSCLC): final results from non-squamous (NSQ) pts (NCT01160744) (ID 1471)

      16:15 - 17:45  |  Author(s): R.C. Doebele, D. Spigel, M. Tehfe, S. Thomas, M. Reck, S. Verma, S. Yurasov, D.R. Camidge, P. Bonomi

      • Abstract
      • Presentation
      • Slides

      Background
      Vascular endothelial growth factor (VEGF)-mediated angiogenesis plays an important role in NSCLC pathogenesis. RAM is a human IgG1 monoclonal receptor targeted antibody that inhibits VEGF receptor-2 (VEGFR-2) binding and signaling. This study investigates RAM in combination with first-line platinum-pemetrexed chemotherapy in advanced NSCLC.

      Methods
      Eligible patients had Stage IIIb/IV NSCLC, ECOG PS ≤ 2, and no prior chemotherapy or VEGF/VEGFR therapy for metastatic disease. Non-squamous (NSQ) pts with advanced NSCLC were randomized 1:1 to either Arm A: pemetrexed + carboplatin/cisplatin (PEM + Cb/Cis) followed by PEM maintenance or Arm B: Ramucirumab 10 mg/kg + pemetrexed + carboplatin or cisplatin (RAM + PEM + Cb/Cis), followed by RAM + PEM maintenance once every 3 weeks. Patients received the first-line therapy from 4 to 6 cycles (21-day cycle); patients without evidence of disease progression entered a maintenance phase. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), change in tumor size, duration of response, and safety.

      Results
      From Oct 2010 to 2012, 140 pts were randomized (PEM + Cb/Cis: 71; RAM + PEM + Cb/Cis: 69). Overall, baseline patient characteristics were balanced between arms. The median PFS was 5.6 m PEM + Cb/Cis and 7.2 m for RAM + PEM + Cb/Cis; HR 0.75 (90% CI, 0.55, 1.03; p =0.132). ORR (CR + PR) was 38% for PEM + Cb/Cis and 49.3% including one complete response in the RAM + PEM + Cb/Cis arm (p=0.18). Disease control rate (CR + PR + SD) was 70% PEM + Cb/Cis and 86% for RAM + PEM + Cb/Cis ( p = 0.031). Median OS at the time of final PFS analysis was 10.4 m for PEM + Cb/Cis and 13.9 m for RAM + PEM + Cb/Cis; HR 0.83 (90% CI, 0.56, 1.22; p=0.43). Grade ≥ 3 adverse events (AEs) occurring in >10% of patients on RAM containing arm were: anemia, neutropenia, thrombocytopenia, nausea, fatigue, back pain, and hypertension.

      Conclusion
      While the primary endpoint of significant prolongation of PFS was not met, RAM has evidence of clinical activity in combination with PEM + Cb/Cis in patients with NSQ NSCLC. Addition of RAM to PEM + Cb/Cis did not result in excessive or unexpected toxicity.

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      MO06.09 - DISCUSSANT (ID 3938)

      16:15 - 17:45  |  Author(s): R. Pirker

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO06.10 - Phase II study of bevacizumab, cisplatin and docetaxel plus maintenance bevacizumab as first line treatment for patients with advanced non-small cell lung cancer (n-Sq NSCLC) combined with exploratory analysis of circulating cells (CEC): Thoracic Oncology Research Group (TORG)1016 (ID 1211)

      16:15 - 17:45  |  Author(s): K. Katono, T. Kato, N. Masuda, F. Oshita, Y. Hosomi, M. Nishikawa, T. Kaburagi, H. Okamoto, S. Morita, K. Watanabe

      • Abstract
      • Presentation
      • Slides

      Background
      Bevacizumab has been shown to amplify efficacy against n-Sq NSCLC in combination with platinum doublet, especially taxane including regimens. Docetaxel is one of best taxane composition combined with cisplatin for first line treatment for NSCLC, and known to have anti-angiogenic effect and may act synergistically with VEGF inhibiting agent. The object of this study was to assess the efficacy and safety of bevacizumab, cisplatin and docetaxel combination treatment in patients with chemonaive n-Sq NSCLC patients. (Trial Registry: UMIN 000004368)

      Methods
      Eligible patients had advanced or recurrent n-Sq NSCLC with no prior chemotherapy. Patients having brain metastasis or history of hemoptysis were ineligible. Patients received 4 cycles of docetaxel (60mg/m[2]), cisplatin (80mg/m[2]) and bevacizumab (15mg/kg) on day1 every 3 weeks followed by Bev alone as maintenance every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was response rate (RR) and planned sample size of this phase II study was 47 patients (Simon's two-stage minimax design). We measured circulating endothelial cells (CEC) count day1 and 8 of first cycle for exploratory analysis of efficacy and safety prediction.

      Results
      From Oct 2010 to Apr 2012, 47 patients (28 males/ 19 females, median age, 61 years, 39-73) were enrolled. Stage IIIB/IV/recurrent: 5/39/3, ECOG PS 0/1: 31/16. All patients were adenocarcinoma, EGFR status: mutated/wild/unknown: 13/31/3. Bevacizumab maintenance were administered in 87% (41/47) of the patients and 9 was median number of delivered course, 4 course of induction and 5 course of maintenance. Dose reduction was required in 28% (13/47) of the patients. Thirty-five partial responses and 11 stable diseases were observed among 47 patients, yielding a RR of 74.5% (95% confidence interval: 59.7-86.1%) and disease control rate of 97.9% (88.7-99.9%), respectively. The median progression free survival duration in the patients was 9.0 (7.0-11.3) months. Grade 3/4 leukopenia, neutropenia, hypertension, nausea and febrile neutropenia were observed in 60, 96, 47, 13 and 9% of the patients, respectively. Alveolar hemorrhage (Grade 5) after 4 cycle occurred in one patient.

      Conclusion
      Bevacizumab, cisplatin and docetaxel combination followed by bevacizumab maintenance treatment was highly effective in patients with n-Sq NSCLC, with acceptable toxicity. Exploratory analysis of CEC is ongoing and will be presented.

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      MO06.11 - A Phase II Trial of Paclitaxel, Pemetrexed and Bevacizumab in Patients with Untreated, Advanced Lung Cancers (ID 3142)

      16:15 - 17:45  |  Author(s): M.C. Pietanza, M.D. Hellmann, N. Rizvi, C.G. Azzoli, S. Smith-Marrone, J. Fiore, L.B. Tyson, D.K. Sumner, A.B. Hergianto, S.L. Kass, C.P. Miller, C.S. Sima, B. Zhao, M.S. Ginsberg, L.H. Schwartz, M.G. Kris

      • Abstract
      • Presentation
      • Slides

      Background
      Standard front-line treatment for patients with unresectable or metastatic non-small cell lung cancer (NSCLC) is a platinum-based doublet with bevacizumab regimen, which achieves objective response rates (ORR) of 35% and median survival of 12 months. However, many patients with lung cancer are not eligible for cisplatin because of baseline neuropathy, hearing loss, renal insufficiency, or comorbid medical conditions. Although carboplatin is often substituted for cisplatin, it also is associated with similar toxicities, albeit with a smaller risk. This phase II trial of paclitaxel, pemetrexed, and bevacizumab was designed to avert the toxicities of platinum-based chemotherapeutic regimens and determine the efficacy of such a "non-platinum" containing doublet with bevacizumab.

      Methods
      Patients with untreated, advanced NSCLCs were enrolled if they had measurable disease (RECIST 1.0) and adequate organ and marrow function. Patients were excluded if they had squamous cell carcinoma; hemoptysis; symptomatic or hemorrhagic brain metastases; history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess; and myocardial infarction or stroke within 6 months prior to enrollment. For six 28-day cycles, patients received: paclitaxel 90 mg/m[2] (days 1, 8, and 15), pemetrexed 500 mg/m[2] (days 1 and 15), and bevacizumab 10 mg/kg (days 1 and 15). Patients with response or stable disease continued pemetrexed and bevacizumab every 14 days until progression or unacceptable toxicity. Patients were evaluated on days 1, 8 and 15 of each 28-day cycle. To assess response, CT scans were performed after cycles 1 and 2, and every 2 cycles thereafter. ORR was the primary endpoint.

      Results
      Forty-four patients were enrolled: 50% women, median age of 59 years (range, 31 to 77), 89% with Karnofsky performance status ≥80%. Mutation status was known in 38 patients (KRAS, n=16; ALK, n=3; BRAF V600E, n =2; Her2 insertion/PIK3CA, n=1; EGFR Exon 20 insertion, n=1; none, n=15). The ORR was 52% (95% CI, 37-68), with 23 partial responses and no complete responses. The median overall survival and progression-free survival were 17 months (95% CI, 12-33) and 8 months (95% CI, 6-12), respectively. Grade 3/4 toxicities included fatigue (33%); elevated liver function tests (15%); leukopenia (9%); hoarseness (7%); nausea (7%); and anemia (7%). Two patients died on study of respiratory failure, possibly related to therapy. No bleeding events were noted.

      Conclusion
      The “non-platinum” containing regimen of paclitaxel, pemetrexed and bevacizumab is an effective first-line treatment for patients with advanced NSCLCs, regardless of mutational status. Long survival was observed, with acceptable toxicities. This regimen warrants further study.

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      MO06.12 - Efficacy and safety of paclitaxel and carboplatin with bevacizumab for the first-line treatment of patients with nonsquamous non-small cell lung cancer (NSCLC): analyses based on age in the phase 3 PointBreak and E4599 trials (ID 2879)

      16:15 - 17:45  |  Author(s): C.J. Langer, M.A. Socinski, J.D. Patel, A.B. Sandler, J.H. Schiller, L. Leon, S. Hazard, S.S. Ramalingam

      • Abstract
      • Presentation
      • Slides

      Background
      A post hoc analysis of NSCLC patients (pts) aged ≥70 y in the pivotal E4599 trial found increased adverse events (AEs) and numerically decreased overall survival (OS) benefit associated with bevacizumab (BEV) compared with pts <70 y. We evaluated the efficacy and safety of BEV by age in pts in a pooled dataset from the E4599 and PointBreak (PB) trials.

      Methods
      Pts randomized to the PC (paclitaxel and carboplatin ) + BEV arms of E4599 and PB received P 200 mg/m[2], C AUC 6, and BEV 15 mg/kg q3w for 6 (E4599) or 4 (PB) cycles; Eligible pts received maintenance BEV alone q3w until disease progression or unacceptable toxicity. OS, progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety were assessed in pts grouped according to age (<65 y, 65–74 y, 70–74 y, <75 y, and ≥75 y). Pt-level data from the PC + BEV arms of E4599 and PB were pooled and compared with data from pts in the PC-alone arm of E4599.

      Results
      PB and E4599 randomized 467 pts and 434 pts to PC + BEV, respectively, while 444 were randomized to receive PC alone on E4599. Baseline characteristics were balanced between age groups. OS and PFS hazard ratios (HRs) and increases in grade ≥3 AEs for the pooled pt cohort relative to E4599 PC-alone arm are shown (Table). Outcomes were similar in pts <70 y and ≥70 y, and data from the pooled population were similar to those seen in each individual trial (data not shown). ORR for pts <75 y was 39% with PC + BEV vs 26% with PC (P<.01). For pts ≥75 y, ORR was 33% vs 30% (P=.71). DCR in pts <75 y was 70% with PC + BEV vs 53% with PC (P<.01). For pts ≥75 y, DCR was 60% vs 67% (P=.37).

      Conclusion
      In a pooled exploratory analysis of pt data from E4599 and PB, the statistically significant benefit associated with the addition of BEV to PC appeared consistent across all age groups <75y, while pts ≥75 y receiving PC + BEV had no statistically significant survival benefit. Pts receiving PC + BEV had an increase in grade ≥3 AEs compared with pts receiving PC-alone in all age groups.

      PB + E4599 <65 y n=735 65–74 y n=453 70–74 y n=203 <75 y n=1188 ≥75 y n=157
      HR for OS 95% CI P 0.75 0.62–0.89 <.01 0.80 0.64–1.00 .05 0.68 0.48–0.96 .03 0.78 0.68–0.89 <.01 1.05 0.70–1.57 .83
      HR for PFS 95% CI P 0.71 0.60–0.85 <.01 0.62 0.49–0.78 <.01 0.68 0.48–0.96 .03 0.69 0.60–0.79 <.01 0.95 0.62–1.44 .80
      E4599 n=499 n=277 n=129 n=776 n=102
      Δ Grade ≥3 AEs,[a ]% P 13 <.01 21 <.01 23 <.01 15 <.01 25 <.01
      [a]Relative to PC-alone arm.

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      MO06.13 - BEYOND: a randomized, double-blind, placebo-controlled, multicentre, phase III study of first-line carboplatin/paclitaxel (CP) plus bevacizumab (Bv) or placebo (Pl) in Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) (ID 2756)

      16:15 - 17:45  |  Author(s): C. Zhou, G. Chen, X. Liu, Y. Zhu, S. Lu, J. Feng, J. He, B. Han, J. Wang, G. Jiang, C. Hu, H. Zhang, G. Cheng, X. Song, Y. Lu, H. Pan, W. Zheng, A. Yin, Y. Wu

      • Abstract
      • Slides

      Background
      Bevacizumab, a monoclonal antibody that inhibits angiogenesis via the vascular endothelial growth factor (VEGF) pathway, has proven efficacy in extending overall survival (OS) (Sandler et al, 2006) and progression-free survival (PFS) (Sandler et al, 2006; Reck et al, 2009) when added to platinum-doublet chemotherapy as first-line treatment for advanced non-squamous NSCLC. These pivotal studies included mainly Caucasian patients, however subgroup analyses in Asian patients also reported efficacy of the first-line Bv+CP regimen (Reck et al, 2009). The BEYOND study was initiated to confirm efficacy in a Chinese population.

      Methods
      Patients aged ≥18 years with histologically or cytologically confirmed, locally advanced, metastatic or recurrent advanced non-squamous NSCLC and an ECOG performance status of 0–1 were randomised 1:1 to receive CP (paclitaxel 175mg/m[2] i.v. and carboplatin AUC6 i.v. on day 1 of each 3-week cycle for up to 6 cycles), plus either Pl or Bv 15mg/kg i.v. on day 1 of each cycle, until progression, unacceptable toxicity, withdrawal of patient consent or death. Patients had no prior treatment for advanced NSCLC. Patients were stratified by gender, smoking status and age. The primary endpoint was PFS in the intent-to-treat (ITT) population; secondary endpoints included objective response rate (ORR), OS, exploratory biomarkers and safety. Collection of blood samples for biomarker analyses was mandatory (at baseline, every two cycles during treatment, at progression, and 4–6 weeks post-progression); tissue samples were optional.

      Results
      276 patients were randomised into the study, 138 to each arm. Baseline characteristics were similar in both treatment groups. PFS was prolonged with Bv+CP versus Pl+CP: hazard ratio 0.40 (95% CI 0.29–0.54); median 9.2 versus 6.5 months; p<0.0001 (ITT population). ORR was also improved with the addition of Bv to CP: 54.4% versus 26.3% with Pl+CP. Disease control rate was 94.4% versus 88.7% with Bv+CP and Pl+CP, respectively. Median duration of response was 8.0 months with Bv+CP versus 5.3 months with Pl+CP. OS data are not yet mature. Safety data were similar to previous studies of Bv+CP in NSCLC; no new safety signals were observed. Treatment discontinuation due to adverse events was 18.4% (Bv+CP) and 15.0% (Pl+CP). Treatment-related deaths were low in both arms (Bv+CP: 2.2%; Pl+CP: 0.0%). Detailed safety data and biomarker analyses will be reported.

      Conclusion
      This study confirms that the addition of bevacizumab to first-line platinum-based chemotherapy appears to provide similar PFS benefits in Chinese patients with advanced non-squamous NSCLC compared with global populations. No new safety concerns were reported.

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      MO06.14 - DISCUSSANT (ID 3939)

      16:15 - 17:45  |  Author(s): W.E.E. Eberhardt

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 12
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      MO15.01 - Pathway activation mapping of KRAS wild type and mutated adenocarcinomas of the lung: new implications for patient stratification for MAP kinase pathway inhibition (ID 2705)

      16:15 - 17:45  |  Author(s): E. Baldelli, E.B. Haura, L. Crino, W..D. Cress, V. Ludovini, M.B. Schabath, G. Bellezza, J. Vannucci, V. Tassi, L. Pistola, F.R. Tofanetti, A. Flacco, A. Siggillino, L.A. Liotta, E.F. Petricoin, M. Pierobon

      • Abstract
      • Presentation
      • Slides

      Background
      KRAS proto-oncogene is one of the most frequent mutated genes in Non-Small Cell Lung Cancer (NSCLC) with greater incidence among adenocarcinomas (AD). While the clinical importance of KRAS mutation as a negative predictor for anti-EGFR therapy is not clearly understood in NSCLCs, selection of targeted therapies for KRAS mutated (MUT) patients has often focused on the inhibition of its direct downstream effectors. The aim of this study was to explore the impact of the KRAS status on the cellular signaling network of ADs of the lung harboring different KRAS mutations with a focus on ERK signaling architecture.

      Methods
      A total of 58 AD samples were collected from chemo-naïve patients at the H. Lee Moffitt Cancer Center & Research Institute (Tampa, FL) and at S. Maria della Misericordia Hospital (Perugia, Italy). Twenty-four tumors were KRAS wild type (WT) and 34 were KRAS MUT (G12C n=18, G12V n=9, G13D n=3 and G12D n=4, respectively). All samples were subjected to laser capture microdissection and reverse phase protein microarray to quantitatively evaluate the activation status of the MAP Kinase signaling network.

      Results
      Statistical analysis of signaling protein activation based on KRAS status revealed an overall increase in activation level of the MAPK signaling network in the KRAS MUT tumors compared to tumors expressing KRAS WT: ERK 1/2 (T202/Y204), Elk-1 (S383), p90RSK (S380), Smad2 (S245/250/255) and p70S6K (p<0.01; p<0.01; p<0.01, p=0.04 and p<0.01 respectively). Nevertheless, 6 KRAS WT patients (25%) showed activation of ERK greater than the median of the entire population and an overall MAPK signaling activation comparable to tumors harboring KRAS MUT. Eleven of the KRAS MUT tumors (32%) had ERK activation lower than the median of the population as a whole. Interestingly a high activation level of Estrogen Receptor alpha (ERα) (S118) was detected in the KRAS MUT tumors compared to the KRAS WT one (p=0.02). Moreover the nonparametric test performed to establish the correlation of activated ERK 1/2, Raf, B-Raf, C-Raf and Mek 1/2 with the expression/activation levels of the 152 endpoints analyzed in this study, revealed the activation of distinct pathways in the KRAS MUT tumors when compared to KRAS WT tumors. Significant correlations were detected with Akt, KRAS, their downstream substrates and with several receptor tyrosine kinases (p<0.0003).

      Conclusion
      Our results suggest that MAPK signaling activation was clearly observed in KRAS MUT tumors. However, the heterogeneity in the activation level of MAPK downstream substrates within KRAS MUT and WT tumors suggests that selection of patients for MAPK targeting might benefit from the evaluation not only of the mutation itself, but also from a direct analysis of the MAPK protein network architecture. In particular the role played by ERα in KRAS MUT tumors deserves further investigations as a possible novel therapeutic target in KRAS MUT adenocarcinomas of the lung.

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      MO15.02 - Impact of co-occurring genetic events on the signaling landscape of KRAS-mutant lung adenocarcinoma. (ID 2936)

      16:15 - 17:45  |  Author(s): F. Skoulidis, L. Diao, Y. Fan, J.D. Minna, J.N. Weinstein, J. Wang, J.V. Heymach, L.A. Byers

      • Abstract
      • Presentation
      • Slides

      Background
      Personalized medicine frameworks centered on identification and therapeutic targeting of dominant oncogenic driver mutations are rapidly becoming a standard of care in the clinical management of patients with lung adenocarcinoma. However, little is currently known about the nature and impact of co-occurring genetic events on signaling output downstream of initiating oncogenes. This lacuna in our understanding is particularly pertinent for the subgroup of KRAS-driven tumors, where mounting data point towards considerable heterogeneity in pathway activation and clinical response to targeted therapies. Here, we report a comprehensive analysis of genetic events that co-occur with or are mutually exclusive of mutant KRAS in a cohort of 230 lung adenocarcinomas and assess the impact of individual co-mutations on signaling streams using data derived from state of the art transcriptomic and (phospho)proteomic profiling of primary tumors.

      Methods
      An integrated analysis of 230 lung adenocarcinomas from The Cancer Genome Atlas (TCGA) consortium was performed using mutation (whole exome sequencing), transcriptomic (RNASeq), and proteomic (reverse phase protein array) datasets. Fischer’s exact test was applied to identify secondary mutations that occurred more frequently in either KRAS-mutant (n=68) or KRAS-wild-type (n=162) tumors and (phospho)protein markers that associated with each co-mutation. Genes with a mutation rate of ≥3% in the overall cohort were included in the analysis.

      Results
      Mutations in 18 genes were associated with KRAS mutational status in patient tumors (p≤0.01). Mutations in EGFR (p=0.0001), NF1 (p=0.001), and TP53 (p=0.001) were negatively correlated with the KRAS mutation. On the other hand, mutations in STK11 were significantly more frequent in the KRAS-mutant cohort (p=0.004), as were mutations in ATM (p=0.023) and MTOR (p=0.045). The most significant positive association involved mutations in ARHGEF11, a gene that encodes a Rho guanine nucleotide exchange factor (p=0.0004). Mutations in STK11 (29.4%) and TP53 (29.4%), the two most highly prevalent genetic events within the KRAS-mutant cohort were mutually exclusive. Unsupervised hierarchical clustering of transcriptomic and quantitative (phospho)proteomic profiles revealed separation of STK11-mutant tumors at the first branch of the cluster dendrogram, indicating activation of distinct signaling pathways downstream of this key tumor suppressor gene. Several less frequent genetic events had prominent and consistent effects on signaling output. We focused our attention on signaling via the MAPK pathway which may impact clinical sensitivity to MEK inhibitors, one of the most promising classes of targeted agents currently in clinical development for KRAS-mutant tumors. Preliminary analysis suggests that mutations in 3 individual genes can identify a subgroup of tumors (19% of the cohort) with profoundly suppressed MAPK signaling flux.

      Conclusion
      Analysis of recurrent secondary genetic events may define distinct and clinically relevant subsets of KRAS-mutant lung adenocarcinoma. Efforts to refine the sub-classification further and assess the impact of co-mutations on sensitivity to molecularly targeted agents are underway and updated results will be presented at the meeting.

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      MO15.03 - Deciphering the RASSF1A signaling pathway in lung cancer cells reveals a metastasis-suppressor role through YAP-dependent epithelial-mesenchymal transition (EMT) (ID 3189)

      16:15 - 17:45  |  Author(s): G. Zalcman, F. Dubois, M. Keller, E. Bergot, A. Hergovich, J. Camonis, G. Levallet

      • Abstract
      • Presentation
      • Slides

      Background
      RASSF1A gene promoter hypermethylation was previously shown to predict poor overall survival in the IFCT-0002 randomized phase 3 trial of neo-adjuvant platinum-based chemotherapy, in early stage (I & II) NSCLC. We investigated the molecular and cellular basis for such a dramatic influence.

      Methods
      We studied isogenic immortalized bronchial, non-tumorogenic, HBEC3 cell lines only differing by their K-Ras status (wild-type or mutant K-Ras Val12 allele), and a panel of lung cancer cell lines recapitulating the main molecular alterations encountered in lung cancer. RASSF1A protein was depleted by 80% using 2 specific siRNAs, followed by the evaluation of EMT markers and cell motility regualors using qRT-PCR, Western blot or Immunofluorescence. Migration of transfected cells was assayed by 2D wound-healing migration assays or 3D migration assays using transwell devices with or without a matrigel coating mimicking basement membrane (invasion assay), or an endothelial cell monolayer (trans-endothelial cell invasion). Phenotypic rescue was studied by using plasmids encoding full-length RASSF1A or RASSF1C isoform, and a construct encoding a SARAH-deleted RASSF1A protein, unable to interact with the Hippo/MST kinase. We also tested co-transfection of RASSF1A siRNAs together with siRNAs directed against Hippo pathway members LATS1/2, WW45, YAP. Depletion of RASSF1A was finally combined with expression of wild-type, activated or dominant negative RhoA, RhoB, Rac1 or CDC42 constructs.

      Results
      In each bronchial/lung cancer cell line tested, RASSF1A silencing led to EMT resulting in E-cadherin, Syndecan1, Zo-1, miR200 decrease and concurrent N-cadherin, vimentin, Twist1, miR-21 increase. RASSF1A silencing-induced EMT was associated with cytoplasmic to nucleus translocation of YAP transcription factor, the terminal effector of the Hippo signaling pathway. RASSF1A silencing reduced cell adhesion and increased 2D cell motility with collective migration features. RASSF1A knock-down increased 3D migration, invasion as trans-endothelial migration. These effects correlated with the up-regulation of RhoA, RhoC, CDC42, MMP2/14 mRNAs and down-regulation of RhoB, DIA1 and MMP9 mRNAs. We also observed an increase of adhesion/invasion signaling proteins, i.e. CD44v6, cofilin, ERM and NF2, cofilin being activated by inhibition of LIMK-induced phosphorylation. Finally we report that immortalized non-tumorogenic cell lines, unable to grow without adhesion, acquired the capacity to grow in soft agar when RASSFIA was knocked-down. Those effects were rescued by co-transfection of RASSF1A siRNAs with full-length RASSF1A cDNA, showing the specificity of the motile phenotype induced by RASSF1A silencing, but not by RASSF1C nor SARAH-deficient RASSF1A plasmids. SiRASSF1A-induced cell migration was inhibited by LATS1/LATS2/WW45 or YAP siRNAs, showing the involvement of the Lats/YAP signaling cascade. We finally show that RASSF1A knockdown-promoted migration was inhibited by using RhoB-Val14 constitutively active cDNA but not RhoBN19 dominant negative construct, and by specific RhoB GEFs or RhoB effectors (DIA1) constructs.

      Conclusion
      In lung cells, the RASSF1A protein acts as a migration-suppressor protein by regulating the LIMK/cofilin pathway through RhoB signaling. RASSF1A prevents YAP induced EMT by inhibiting its nuclear accumulation through LATS1/2 signaling, whereas Hippo/MST kinase seemed dispensable. We thus provide evidence, for the first time in human lung cancer cells, for a direct connection between RASSF1A signaling and the LATS/YAP pathway.

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      MO15.04 - Loss of Tumor Suppressor Hic1 Accelerates the Progression of Lung Adenocarcinoma Induced by Oncogenic KRas (ID 2655)

      16:15 - 17:45  |  Author(s): A. Szczepny, S. Jayasekara, A. Mudiyanselage, D.N. Watkins

      • Abstract
      • Presentation
      • Slides

      Background
      Hypermethylated in Cancer-1 (Hic1) is a novel tumour suppressor gene that is frequently epigenetically silenced in adult tumours. In non-small cell lung cancer (NSCLC), loss of Hic1 expression is associated with reduced patient survival, suggesting reduced Hic1 expression is associated with malignant progression of NSCLC. However, whether Hic1 silencing is causal in lung cancer is not known. Hic1 is a transcriptional repressor that can regulate p53 function by repressing the expression of SIRT1, a class III histone deacetylase. We therefore hypothesized that loss of Hic1 function could cooperate with an oncogenic mutation in KRas (KRasG12D) to promote lung cancer initiation and/or progression in a similar fashion to genetic deletion of p53.

      Methods
      To address this question, we used a conditional genetic mouse model of lung adenocarcinoma in which administration of recombinant adenovirus expressing Cre can trigger recombination at loxP sites. When virus is administered to mice heterozygous for a conditional KRasG12D allele, mice develop multiple lung adenomas that progress to adenocarcinomas over 8-12 weeks. To test the function of Hic1 as a tumour suppressor, we created a conditional knockout mouse allele (Hic1[lox]), in which loxP sites flank the single coding exon.

      Results
      Following administration of Cre adenovirus, mice carrying the KRasG12D allele and homozygous for the Hic1[lox] allele, developed aggressive lung adenocarcinomas at a markedly accelerated rate and had a significantly shortened survival compared to KRasG12D animals. Remarkably, these tumours exhibited a highly malignant phenotype with highly proliferative micropapillary and pleomorphic features.

      Conclusion
      These data show that loss of Hic1 function can substitute for p53 mutation as a cooperating event in lung adenocarcinoma progression. Since the highly aggressive phenotype of KRasG12D/Hic1[lox/lox] lung tumours has not been reported in the KRasG12D/p53[lox/lox] lung cancer model, we speculate that Hic1 may function as a tumour suppressor beyond the regulation of p53 through Sirt1.

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      MO15.05 - Oncogenic ARAF mutation in lung adenocarcinoma (ID 2860)

      16:15 - 17:45  |  Author(s): M. Imielinski, H. Greulich, B. Kaplan, L. Araujo, J. Amann, L. Horn, M. Villalona-Calero, M. Meyerson, D.P. Carbone

      • Abstract
      • Presentation
      • Slides

      Background
      Targeted cancer therapies often induce “outlier” responses in molecularly defined patient subsets.

      Methods
      One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a complete clinical and radiographic remission for five years. Whole genome sequencing (WGS) and RNA sequencing (RNA-seq) on primary tumor and normal samples from this patient was performed.

      Results
      We identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF mutants were shown to transform immortalized human airway epithelial cells and were associated with in vitro sorafenib sensitivity.

      Conclusion
      These results suggest that mutant ARAF may be a novel oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.

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      MO15.06 - A prospective internet-based study of patients with lung cancer harboring baseline EGFR T790M to identify germline carriers and characterize familial risk (ID 1667)

      16:15 - 17:45  |  Author(s): G.R. Oxnard, J.C. Heng, I.R. Rainville, A.L. Sable-Hunt, E.J. Root, G.L. Wiesner, D.P. Carbone, P.A. Jänne, J.E. Garber

      • Abstract
      • Presentation
      • Slides

      Background
      The EGFR T790M mutation, commonly seen with acquired resistance to EGFR kinase inhibitors, has also been described rarely as a germline mutation in association with familial lung cancer. In a prior study (Oxnard et al, JTO, 2012), the presence of EGFR T790M at diagnosis was associated with a 50% chance of carrying an underlying germline T790M mutation. This suggests that by studying patients whose cancer was shown to carry T790M at diagnosis, it is possible to efficiently screen for a germline allele that otherwise is rare among patients with non-small cell lung cancer. We therefore initiated a prospective trial to identify patients and families carrying germline EGFR mutations in order to characterize phenotype and cancer risk.

      Methods
      Subjects are eligible if they (1) have a cancer harboring EGFR T790M (excluding acquired T790M), (2) are a relative of a known germline carrier, or (3) are already known to carry a germline EGFR mutation on prior testing. Subjects may present at a participating cancer center or may enroll remotely using a study website (www.dana-farber.org/T790Mstudy/). Eligible subjects receive genetic counseling in person or over the phone, and then submit a saliva and/or blood specimen for central testing in a CLIA lab. Results are disclosed to the subject if they wish but do not enter the medical record. Those subjects carrying germline EGFR mutations are given the option of inviting relatives to participate. Chest CT scans are collected from germline carriers and analyzed centrally to study nodule prevalence and characteristics. Available tumor specimens are collected for central pathology review and advanced genomic analysis.

      Results
      The trial was registered to clinicaltrials.gov (NCT01754025) and began accrual in December 2012. To date, 7 subjects have been enrolled and 5 are actively being screened, including 4 kindreds. More than half of the subjects have participated remotely via the study website. Of 4 probands with lung cancer and germline T790M, 3 have a family history of lung cancer, 2 of whom have children with CT scans showing multiple sub-centimeter ground-glass nodules. The fourth proband has no family history of lung cancer, suggesting variable penetrance or a de novo germline event. All cancers in germline T790M carriers have also harbored secondary EGFR kinase domain mutations.

      Conclusion
      Using a novel trial design, including remote accrual, genetic counseling by phone, and germline testing by mail, we have begun collecting a sizeable cohort of families affected by germline EGFR mutations. By leveraging referrals from commercial laboratories and contributing academic centers, we aim to study 100 patients over a three year period in order to better understand the natural history and risk associated with this unique familial cancer syndrome. Supported by grants from the Conquer Cancer Foundation of ASCO, the Bonnie J. Addario Lung Cancer Foundation, and the National Cancer Institute.

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      MO15.07 - DISCUSSANT (ID 3898)

      16:15 - 17:45  |  Author(s): G. Riely

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO15.08 - KDR (VEGFR-2) copy number gains and mutations are targetable alterations in non-small cell lung cancer (ID 1466)

      16:15 - 17:45  |  Author(s): M.B. Nilsson, T. Cascone, U. Giri, J. Gudikote, L. Diao, A. Koo, H. Lu, T. Dogruluk, E. Riquelme, X. Tang, H.T. Tran, K. Scott, I.I. Wistuba, D. Carbone, M.A. Socinski, J.V. Heymach

      • Abstract
      • Presentation
      • Slides

      Background
      Therapeutic regimens targeting the vascular endothelial growth factor (VEGF) pathway have been extensively tested in the treatment of malignancies including non-small cell lung cancer (NSCLC). VEGF pathway inhibitors including bevacizumab or VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have been shown to prolong progression-free survival (PFS) and/or overall survival (OS). These benefits, however, have been modest, occurring only in subsets of patients. Therefore, predictive markers to identify patients likely to derive benefit are critically needed. Although expression of VEGFR-2, also known as KDR, was initially thought to localize primarily on endothelial cells, VEGFR-2 has been detected on malignant cells. We recently observed that KDR copy number gains (CNGs) were detectable by FISH in ~30% of both adenocarcinoma and squamous cell carcinoma and were associated with poor clinical outcome in early stage NSCLC patients treated with adjuvant chemotherapy. In addition to CNGs, mutations and polymorphisms within the KDR gene were also observed. The impact of these alterations is unknown. Here, we investigated KDR CNGs, polymorphisms, and mutations in NSCLC and their effects on sensitivity to VEGFR targeting agents in preclinical models and in NSCLC patients.

      Methods
      Cell migration was evaluated by Boyden chamber assay. NSCLC cell lines were treated with VEGF pathway inhibitors for 24 hours, and protein lysates where collected. HIF-1α levels were evaluated by ELISA assay. VEGFR, p38, and p70s6K were evaluated by Western blotting. Tumor DNA and peripheral blood DNA, were analyzed in duplicate using Affymetrix Genome-Wide SNP Array 6.0. Transformation of Ba/F3 cells was evaluated by an IL-3-independent growth assay.

      Results
      In tumor cells with KDR CNG, VEGF stimulation induced activation of p38 and p70S6K, and VEGFR TKIs including sorafenib and vandetanib effectively inhibited VEGF-mediated signal transduction. In tumor cell lines with KDR CNG, exogenous VEGF ligand increased cell motility and this was inhibited by VEGFR blockade with TKIs including sunitinib, sorafenib, and axitinib. Various receptor tyrosine kinases have been shown to drive HIF-1α levels, and NSCLC cells with KDR CNG express elevated levels of HIF-1α in normoxia compared to NSCLC cell lines without KDR CNG. In NSCLC cell lines with KDR CNG, VEGFR TKIs decreased protein levels of HIF-1α and HIF-1α regulated proteins. Furthermore, we report a clinical case in which a NSCLC patient with KDR CNG had a partial response to the VEGFR inhibitor, sorafenib. In addition to gene amplification, mutations and polymorphisms within the KDR gene were also observed. KDR mutation 1586A>T and polymorphism 1416A>T effectively transformed Ba/F3 cells. Finally, we report two clinical cases in which NSCLC patients with the 1416A>T polymorphism had a partial response the VEGF pathway inhibitor, bevacizumab.

      Conclusion
      Collectively, our data indicate that KDR amplification promotes downstream signaling events including activation of the p38, mTOR, and HIF pathways and are targetable by VEGF pathway inhibitors. KDR gene alterations may be predictive markers for VEGF pathway inhibitors.

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      MO15.09 - Amplification of YEATS4, a novel oncogene in NSCLC, inhibits the p53 pathway and increases resistance to cisplatin (ID 1073)

      16:15 - 17:45  |  Author(s): L. Pikor, W.W. Lockwood, K.L. Thu, E.A. Vucic, R. Chari, A.F. Gazdar, S. Lam, W.L. Lam

      • Abstract
      • Presentation
      • Slides

      Background
      Characterization of lung cancer genomes has revealed a number of genes critical to tumorigenesis (e.g. EGFR, KRAS, EML4-ALK), resulting in significant changes to the treatment of lung cancer and an increase in survival for a subset of patients. These successes have prompted the search for additional driver alterations, leading to the discovery of a number of recurrently mutated or amplified genes and gene fusions with promising clinical utility. Distinguishing the key mechanisms and causal events driving tumorigenesis will lead not only to a better understanding of lung cancer phenotypes and biology, but also to new molecular markers and therapeutic targets. Using an integrative analysis of gene expression and copy number data to identify novel candidate oncogenes, we identified the chromosomal region at 12q13-15, and more specifically, the putative transcription factor YEATS4 (YEATS domain containing 4) as frequently amplified and overexpressed in NSCLC. Amplification of YEATS4 has been reported in dedifferentiated liposarcomas and in the earliest stages of glioma and astrocytoma.

      Methods
      Copy number profiles were generated for 261 NSCLC tumors (169 adenocarcinomas (AC) and 92 squamous cell carcinomas (SqCC)) and expression profiles for a subset of tumors with matched non-malignant tissue. Recurrent DNA amplifications were identified using the GISTIC algorithm. Copy number data were integrated with gene expression data to identify genes frequently amplified and overexpressed (defined as a 2-fold difference in expression between tumor and matched non-malignant tissue). The functional significance of YEATS4 was assessed by lentiviral knockdown in lung cancer cell lines with and without YEATS4 amplification and ectopic expression in human bronchial epithelial cells (HBECs). In vitro and in vivo assays measuring proliferation, anchorage independent growth, senescence, apoptosis, drug sensitivity and tumor growth were used to assess the phenotypic effect of YEATS4 gene expression manipulation.

      Results
      YEATS4 is gained or amplified and concomitantly overexpressed in over 20% of NSCLC tumors, with similar frequencies of amplification in both AC and SqCC. Although frequently co-amplified with MDM2, amplification of YEATS4 was observed to occur in the absence of MDM2 amplification, suggesting it is not merely a passenger event. Overexpression of YEATS4 in HBECs abrogated senescence, whereas knockdown reduced cell proliferation, impaired colony formation and induced cellular senescence in cell lines with YEATS4 amplification. Western blotting revealed increased p21, cleaved PARP and p53 in knockdown lines compared to empty vector controls, implicating YEATS4 as a negative regulator of the p21-p53 pathway. Moreover, YEAST4 expression was found to correlate with cisplatin sensitivity, as overexpression increased resistance and knockdown conferred sensitivity. Consistent with our in vitro findings, tumor size and growth were significantly reduced in mice injected with YEATS4 knockdown cells relative to control mice. Furthermore, survival analysis revealed that patients expressing high levels of YEATS display poorer outcomes.

      Conclusion
      Our findings reveal YEATS4 as a novel candidate oncogene frequently amplified and overexpressed in NSCLC. Gene expression manipulation resulted in distinct phenotypic changes consistent with oncogenic function, and suggesting YEATS4 amplification is a novel mechanism contributing to NSCLC tumorigenesis.

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      MO15.10 - ELF3 is a novel oncogene frequently activated by genetic and epigenetic mechanisms in lung adenocarcinoma (ID 1024)

      16:15 - 17:45  |  Author(s): K.S. Enfield, D.A. Rowbotham, D.D. Becker-Santos, R. Chari, M. Fuller, M. Zhang, M. Suzuki, C.E. Macaulay, A. Karsan, S. Lam, W.L. Lam

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer remains the cause of the most cancer-related deaths each year, with a 5 year survival rate of less than 15%. The predominant type of lung cancer is non-small cell lung cancer, and the majority of these cases consist of the adenocarcinoma (AC) histology. Oncogenes such as EGFR and KRAS are well defined drivers of AC, but in approximately 50% of cases the driver alterations are unknown. Furthermore, not all defined drivers are drugable. Additional oncogenes are clearly involved in driving this subtype, and must be elucidated to better understand AC biology and improve treatment. ELF3 is an member of the E-Twenty Six (ETS) transcription factor family, which includes several well known oncogenes such as ETS1. Expression of ELF3 is uniquely epithelial-specific, with high expression in fetal but not adult lung tissue. ELF3 overexpression has been reported in a handful of clinical AC cases and cell lines, however a comprehensive analysis of the extent and impact of this overexpression is lacking. Therefore we conducted a multi-'omic, functional analysis of ELF3, and hypothesize ELF3 represents a novel oncogene in lung AC.

      Methods
      ELF3 was interrogated in a multidimensional integrative manner by assessing copy number (SNP 6.0), methylation (Illumina HM27), and expression (Illumina) data from a panel of 83 AC tumors and matched adjacent non-malignant tissues. ELF3 expression was also assessed in The Cancer Genome Atlas (TCGA) public database. Stable ELF3 mRNA knock-down models were established in AC cell lines with high ELF3 expression, and these models were used to assess the role of ELF3 in cell viability and proliferation via MTT and BrdU incorporation assay, respectively. Knock-down models were also used to assess the impact of ELF3 overexpression on tumor growth in vitro and in vivo by soft agar colony formation assay and flank injections of NOD-SCID mice. Subcellular localization of ELF3 was determined by western blot and confirmed with immunofluorescence. In addition, an ELF3 overexpression model was established in immortalized Human Bronchial Epithelial Cells (HBECs) to assess proliferation and soft agar colony formation in a non-malignant model system.

      Results
      ELF3 was found to be frequently overexpressed in our cohort (72%) and the TCGA cohort (80%). This upregulation correlated significantly with high frequencies of sequence gain (49%) and hypomethylation (71%), often seen within the same tumor. In fact, 82% of tumors with ELF3 overexpression had concurrent gain and/or hypomethylation of the ELF3 locus. Knock-down of ELF3 in cell models led to significantly reduced cell viability and proliferation. Western blot and IF revealed ELF3 to be predominantly located in the nucleus, indicating ELF3 likely behaves through its transcription factor activity. A similar hyperproliferative phenotype was seen in the HBEC ELF3 overexpression models.

      Conclusion
      The high frequency of ELF3 overexpression (>70%) observed in lung AC is accompanied by frequent DNA-level selection events. The affect of ELF3 on cell proliferation suggests that ELF3 is a novel oncogene in lung AC. Further studies are warranted to determine the mechanism by which ELF3 drives hyperproliferation and potentially other oncogenic functions to define novel drugable targets for this disease.

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      MO15.11 - Using synthetic lethal screening to identify therapeutic targets for innately platinum resistant lung cancer (ID 2629)

      16:15 - 17:45  |  Author(s): K. Marini, F. Rossello, L. Martelotto, N. Watkins

      • Abstract
      • Presentation
      • Slides

      Background
      Although platinum-based chemotherapy is the standard of care for most cases of advanced lung adenocarcinoma, its effectiveness is limited by the frequent incidence of innate chemoresistance. As a result, response rates rarely exceed 20%, even though cis-platinum and carboplatin are highly effective in other settings such as small cell lung, ovarian and testicular cancers. We hypothesized that innate chemoresistance in lung adenocarcinoma is mediated by one or more signalling pathways dependent on the expression of a single gene, and that these pathways could ultimately be targeted therapeutically.

      Methods
      To address this question, we developed a synthetic-lethal high throughput siRNA screen using the innately resistant A549 lung adenocarcinoma cell line. Optimisation of the screen was performed using a siRNA death control (PLK1), which induced cell death in the absence of platinum, and a sensitization control (MTOR), which enhanced cell death only in combination with a sublethal concentration of carboplatin. These independent controls revealed that the screening protocol performed within acceptable limits of variability, quality and reproducibility as determined by Z’ factor analysis. Screening was then performed using a pool of four siRNAs targeting a single gene in conjunction with vehicle treatment, or with carboplatin.

      Results
      After screening siRNAs targeting the 720 kinases, 256 phosphatases and 4794 “druggable” targets of the human genome, we identified 50 candidate targets based on fold change difference between platinum and vehicle treatments, and statistical significance determined by multiple t-test corrected for false discovery rate. Preliminary pathway analysis revealed a highly significant enrichment for genes in previously identified pathways as well as novel pathways.

      Conclusion
      These data demonstrate that a synthetic-lethal approach can be used to identify therapeutic targets that could potentially sensitize lung adenocarcinoma to platinum-based chemotherapy.

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      MO15.12 - DISCUSSANT (ID 3899)

      16:15 - 17:45  |  Author(s): P. Yang

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MO24 - NSCLC - Chemotherapy III (ID 110)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 14
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      MO24.01 - Treatment of elderly (70 years or older) with lung cancer. A four-year material in clinical practice from Karolinska University Hospital - Sweden. (ID 2562)

      10:30 - 12:00  |  Author(s): H. Koyi, E. Brandén, G. Hillerdal

      • Abstract
      • Presentation
      • Slides

      Background
      Sixty percent of all neoplasms and two-thirds of all deaths due to cancer occur in persons older than 65 years. More than 50% of patients with lung cancer are older than 65 years and 30% older than 70 years. With more persons surviving to older age treatment of the elderly with lung cancer has become an important issue.

      Methods
      All patients 70 years or older with non small cell lung cancer (NSCLC) seen at the Department of Respiratory Medicine and Allergy, Karolinska Hospital from 2003 to 2006 were retrospective reviewed. In all 659 patients were analyzed.

      Results
      The mean age was 78 years, 55.5 (%) were men. 93,2% of the males and 82.1% of the females were smokers or former smokers. There was a significant differences between smoking habbits among the genderas (P<0.0001). 77.2 (%) had PS 0-2. 38.4% adenocarcinoma, 9.8% with small cell lung cancer, 20.6% squamous cell carcinoma, 15.6% had clinical lung cancer and the others broncheoalveolar cell carcinoma or low differentiated carcinoma were 15.3%. 10.7% underwent radical surgery, 24% received chemotherapy only, 17.8% radiotherapy against the tumour (there of stereotactic 4.4%), and 3.7% concomitant chemo-radiotherapy. 7.4% received radiotherapy against metastases, and 32.1% had no therapy. Only 10% were given second-line chemotherapy. Median survival for patients 70-75, 76-80 and >80 years was 231, 250 resp 213. Median survival for patients with PS=0 was 810 days, those with PS=3 only 109 days. Median survival was 610 days for patients given second line chemotherapy. Survival among those who received only first line chemotherapy was 285 days.

      Conclusion
      Significant survival among patients given second line chemotherapy (p<0.003). Significant survival among patients between 70-80 versus > 80 years old (P<0.001). Treatment of elderly patients with lung cancer is feasible if they have a good PS and seems to result in prolonged survival.

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      MO24.02 - Treatment decisions for elderly patients with advanced non-small cell lung cancer (NSCLC) in Italian clinical practice: results from the RIGHT-3 project by Italian Association of Medical Oncology (ID 3115)

      10:30 - 12:00  |  Author(s): E. Maiello, S. Barni, A. Ardizzoni, F. Cappuzzo, R. Chiari, E. Maranzano, S. Novello, C. Bennati, M. Di Maio, A. Ori, S. Rizzoli, L. Crino

      • Abstract
      • Presentation
      • Slides

      Background
      In 2004, the Italian Association of Medical Oncology (AIOM) created the RIGHT (Research for the identification of the most effective and highly accepted clinical guidelines for cancer treatment) program. The third step of the program, RIGHT3, aimed to evaluate the concordance between AIOM lung cancer guidelines and clinical practice in Italy. Description of treatment decisions for elderly patients with advanced non-small-cell lung cancer (NSCLC) was among the indicators. According to 2009 AIOM guidelines, single-agent chemotherapy with a third-generation agent was a reasonable choice for elderly patients with advanced NSCLC, whilst evidence about use of platinum-based treatment in the elderly population was judged potentially affected by selection bias and not conclusive.

      Methods
      RIGHT3 was a retrospective observational study conducted in a sample of 53 Italian lung cancer centers, representative of 230 AIOM centers. Patients with NSCLC diagnosis who had their first visit at the oncology center during 2010 and followed-up for at least 6 months were included. Proportion of elderly patients with stage IV disease receiving chemotherapy was among the 14 indicators evaluated.

      Results
      Overall, 306 pts with stage IV NSLSC were enrolled, and 299 were evaluable. Of these, 91 (30.4%) were older than 70. In the elderly subgroup, 81 pts (89%) were treated with first-line chemotherapy. In detail, a single-agent treatment was administered in 28 (34.6%) of cases, and a combination chemotherapy in the other 53 cases (65.4%). Among pts receiving platinum-containing doublets, carboplatin was more frequently used than cisplatin: carbo-gemcitabine (16 pts), carbo-pemetrexed (12 pts), cisplatin-pemetrexed (8 pts), cisplatin-gemcitabine (7 pts), carbo-vinorelbine (4 pts) were the 5 most frequently used regimens.Thirty pts (33%) received a second-line chemotherapy: single-agent in 23 cases, combination chemotherapy in 7 cases.

      Conclusion
      First-line platinum-based combination chemotherapy was commonly used in elderly patients with advanced NSCLC in 2010 by the Italian Lung cancer centers involved. First-line single-agent treatment, recommended by AIOM 2009 guidelines as the treatment choice with highest level of evidence, was used only in a minority of patients.

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      MO24.03 - Treatment of elderly patients ( > 70 years ) with non-small cell lung cancer given chemotherapy. A four-year material in clinical practice from Karolinska University Hospital - Sweden. (ID 3257)

      10:30 - 12:00  |  Author(s): H. Koyi, G. Hillerdal, E. Brandén

      • Abstract
      • Presentation
      • Slides

      Background
      Sixty percent of all neoplasms and two-thirds of all deaths due to cancer occur in persons older than 65 years. More than 50% of patients with lung cancer are older than 65 years and 30% older than 70 years. With more persons surviving to older age treatment of the elderly with lung cancer has become an important issue.

      Methods
      All patients 70 years or older with non small cell lung cancer (NSCLC) given chemotherapy at the Department of Respiratory Medicine and Allergy, Karolinska Hospital from 2003 to 2006 were retrospective reviewed. In all 149 patients were analyzed.

      Results
      The mean age was 75,5 years and median 74 years. 54.4 % were male. 96,3% of the males and 88.2% of the females were smokers or former smokers. There was a significant differences between smoking habitts among the genderas (P<0.05). 16.1% , 50.3% and 27.5% had PS 0 resp 1 resp 2. 57.7% and 30.9% with stage IV resp III . 32.9% adenocarcinoma, 24.8% squamous cell carcinoma, and the others broncheoalveolar cell carcinoma or low differentiated carcinoma were 24.2%. 18.1% of the patients had no histopathological diagnosis – clinical diagnosis. Almost all the patients were given carboplatin/gemcitabin as first line chemotherapy regardless of histology. Four cycles was given to almost all the patients. Only 27.5% were given second-line chemotherapy. Median overall survival was 285 days. Longer overall survival among 70-80 vs > 80 years old patients.

      Conclusion
      Significant survival among patients between 70-80 versus > 80 years old.. Treatment of elderly patients with lung cancer is feasible if they have a good PS and seems to result in prolonged survival.

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      MO24.04 - Assessment of health care patterns for elderly lung cancer patients in Ontario, Canada (ID 1463)

      10:30 - 12:00  |  Author(s): D.E. Dawe, G.R. Pond, P.M. Ellis

      • Abstract
      • Presentation
      • Slides

      Background
      The number of seniors in Canada is expected to double by 2036 and 40% of new cancers are diagnosed in those ≥70 years. New data over the last decade suggests an increasing role for systemic treatment options for elderly lung cancer patients. However, age-related changes in organ function, co-morbid health problems, and a greater risk of death from other causes may impact on toxicity and expected survival gains. Historically, many oncologists excluded older patients from receiving chemotherapy. This study investigated trends in the treatment of NSCLC patients over the last decade contrasting patients ≥70 years to those <70 years old.

      Methods
      We conducted a retrospective cohort study of NSCLC patients (ICD-9 codes 162.2-162.9) residing in Ontario and diagnosed between January 1, 2000-December 31, 2010. Data including demographic, staging, treatment and outcome information were extracted by the Institute for Clinical Evaluative Sciences and de-identified before release. The primary outcomes were the proportion of elderly v non-elderly patients referred to an oncologist and receipt of chemotherapy. Standard statistical methods were used.

      Results
      Of 61,646 patients, 32,131 (52.1%) were ≥70 years. There was an increase in the number and proportion of cases diagnosed in the elderly over the time period. Fewer adenocarcinomas were diagnosed in the elderly (29.8 v 44%) and more elderly patients lacked microscopic confirmation of malignancy (20.1 v 6.2%). Charlson co-morbidity scores and the need for homecare services prior to diagnosis (12.6 v 4.7%) were higher in the elderly. Staging information was inconsistent prior to 2007. In 53.6% of patients, stage was unknown. Stage distribution in remaining patients was: I (18%), II (6%), III (28%), IV (48%). Referral to any lung cancer specialist (defined as medical oncologist, radiation oncologist, or thoracic surgeon) was significantly lower in the elderly population (80.6 vs 93.9%). This was true for each sub-specialty. Only 59.5% of elderly lung cancer patients were referred to a medical oncologist, compared to 78.5% of younger patients. The elderly were less likely to receive chemotherapy (18.3 v 46.7%), even after referral to medical oncology. Elderly patients had a shorter overall (5.8 v 9.6 months) and lung cancer specific survival (9.5 v 13.9 months). Among patients receiving chemotherapy, there was less difference in overall (13.6 v 14.9 months) and lung cancer specific survival (18.6 v 19.9 months). Receipt of chemotherapy increased only marginally among elderly patients between 2000 and 2010. P-values for all comparisons (p<0.001).

      Conclusion
      There is evidence of disparity in treatment of elderly lung cancer patients. Fewer patients ≥70 years old are referred to a lung cancer specialist and receive treatment. This trend is particularly evident for referral to medical oncology and receipt of chemotherapy. In those elderly patients who receive chemotherapy, their survival approximates that seen in younger patients. Published evidence supporting the use of chemotherapy in the elderly does not appear to have been implemented into practice.

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      MO24.05 - DISCUSSANT (ID 3942)

      10:30 - 12:00  |  Author(s): C.J. Langer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO24.06 - Randomized Phase II study of Pemetrexed plus Carboplatin followed by Pemetrexed versus Paclitaxel plus Carboplatin followed by Pemetrexed in Advanced Non-squamous, Non-small Cell Lung Cancer (LOGIK 0904). (ID 2235)

      10:30 - 12:00  |  Author(s): Y. Shiraishi, K. Inoue, M. Takeshita, T. Harada, N. Tashiro, T. Seto, T. Imanaga, N. Fujimoto, N. Nakagaki, M. Kawasaki, J. Kishimoto, K. Takayama, Y. Ichinose

      • Abstract
      • Presentation
      • Slides

      Background
      PARAMOUNT study confirmed the improvement of overall survival with continuation maintenance chemotherapy with pemetrexed (PEM) compared with placebo after 4 cycles of cisplatin plus PEM induction chemotherapy recently. JMEN study also showed the usefulness of switch maintenance with PEM after 4 cycles of platinum doublet without PEM. In this study, we conducted the randomized phase II study comparing switch or continuation maintenance chemotherapy with PEM after standard doublet regimen.

      Methods
      Histologically/cytologically confirmed stage IIIb or IV non-squamous NSCLC patients with mesurable disease, ECOG PS 0-1, age over 20 years and adequate organ function were eligible for the study. Randomization was stratified by gender and stage of disease. Patients received 3 cycles of PEM 500mg/m2 plus CB AUC6 (Arm 1) or PAC 200mg/m2 plus CB AUC6 (Arm 2). All patients with non-PD after induction chemotherapy continued PEM 500mg/m2 until PD. Primary endopoint is progression free survival (PFS).

      Results
      140 pts were enrolled and assigned to Arm1 or Arm2 randomly. The clinical data of 132 pts were used as full analysis set (median age 64.5 yrs (42-83), 85 male, 120 stage IV, 58 PS0, 127 adenocarcinoma, 46 never smoker). 42 pts had prior treatment including 9 sugery, 1 adjuvant chemotherapy, 24 radiotherapy and 8 others. In both arms, 50% of pts entered into the maintenance treatment with PEM after completion of 3 cycles induction chemotherapy. The median PFS was 113 days in Arm 1 and 143 days in Arm 2, respectively. Cox-proportinal Hazard ratio was1.047, and 95% HR confidential interval was 0.707-1.549. Stratified Log-Rank test showed no significant difference in both arms.

      Conclusion
      There was no significant difference for PFS in Arm 1(PEM plus CB followed by PEM) and Arm 2 (PAC plus CB followed by PEM).

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      MO24.07 - nab-Paclitaxel plus carboplatin in patients (pts) with squamous cell (SCC) non-small cell lung cancer (NSCLC): analysis of pts treated beyond 4 cycles in a pivotal phase 3 trial (ID 3438)

      10:30 - 12:00  |  Author(s): M.A. Socinski, D. Spigel, A. Ko, M.F. Renschler

      • Abstract
      • Presentation
      • Slides

      Background
      Continuous maintenance is defined as continuation of ≥ 1 first-line agents after 4-6 cycles of induction therapy in pts who have not progressed. In a pivotal phase 3 trial, first-line treatment to progression with nab-paclitaxel (nab-P, 130-nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C resulted in a 68% improvement in response rate (41% vs 24%; P < .001) and a trend toward improved survival (median, 10.7 vs 9.5 months; P = .808) in the subset of pts with SCC. This unplanned exploratory analysis examined outcomes in pts with SCC receiving > 4 cycles of nab-P/C to assess the feasibility of the nab-P/C regimen in the maintenance setting in SCC.

      Methods
      Pts with untreated stage IIIB/IV NSCLC were randomized 1:1 to nab-P 100 mg/m[2] on days 1, 8, 15 or sb-P 200 mg/m[2] on day 1 every 21 days; both arms received C AUC 6 on day 1. Overall response rate and progression-free survival (PFS) were determined by blinded centralized review. To allow comparison of the results of this analysis with maintenance studies, PFS is expressed from day 1 of cycle 5 (C5D1).

      Results
      229 pts with SCC received nab-P/C and 221 received sb-P/C in this study. In the nab-P/C arm, 60% (n = 138) of pts with SCC were progression-free at the end of cycle 4 and entered cycle 5 (the study population). In these pts, the median PFS was 3.4 months (range 2.8 – 4.2) from C5D1. The median OS from randomization in these pts was 13.8 months (range 12.4 – 16.8). Survival at 1year was 59% (51% – 67%). The median number of treatment cycles was 7 (range 5 – 31). A total of 125 (91%), 64 (46%) and 35 (25%) pts were treated for up to 6, 8 and 10 cycles, respectively, with a median weekly dose of 75 mg/m[2 ]for nab-paclitaxel in each group, and carboplatin AUC of 6, 4.75, and 4.5, respectively. Preliminary safety findings in this population revealed that the most common grade 3/4 treatment-related adverse events were neutropenia (49%), anemia (31%), and thrombocytopenia (27%). The overall rate of grade 3 peripheral neuropathy in the nab-P/C arm was 4% (with no grade 4); 1%, 3%, and 0% of pts had grade 3 peripheral neuropathy at cycle 6, 8, and 10, respectively.

      Conclusion
      Continued treatment with nab-P/C to progression was feasible, well tolerated, and effective in pts with advanced SCC who had not progressed after 4 cycles of first-line therapy. Future randomized, prospective studies are warranted to further evaluate the activity of nab-P/C as maintenance therapy in SCC pts.

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      MO24.08 - Survival outcomes among NSCLC patients in Europe receiving platinum-based therapies as first-line treatment: results from the FRAME observational study (ID 1944)

      10:30 - 12:00  |  Author(s): P. Schnabel, E. Smit, J.D. Castro Carpeño, K. Lesniewski-Kmak, J. Aerts, R. Villatoro, K. Kraaij, C. Visseren-Grul, K. Nacerddine, Y. D'Yachkova, K. Taipale, A. Girvan, D. Moro-Sibilot

      • Abstract
      • Presentation
      • Slides

      Background
      FRAME was a European non-interventional prospective observational study of patients with advanced or metastatic non-small cell lung cancer (NSCLC) initiating platinum-based therapies as first-line treatment (FLT).

      Methods
      Patients were enrolled between April 2009 and February 2011. Consenting adult NSCLC (Stage III/IV) patients initiating FLT with a platinum-based doublet chemotherapy, with or without an additional targeted agent, were eligible for the study. The choice of FLT was left to physician discretion, as per routine clinical practice. The primary objective of FRAME was to evaluate overall survival (OS) among different platinum-based treatment cohorts in patients with and without additional targeted therapy. Secondary objectives included the evaluation of OS in patients with different histological subtypes of NSCLC. Survival outcomes were assessed using Kaplan-Meier analysis, and unadjusted estimates are presented.

      Results
      A total of 1564 eligible patients from 11 EU countries were observed. Patient cohorts were: pemetrexed + platinum, gemcitabine + platinum, vinorelbine + platinum, taxanes + platinum and other therapy + platinum. Table 1 shows a subset of baseline patient characteristics, which varied across several parameters in the treatment cohorts, including age, performance status (PS), stage and histology. The median OS across the 4 main treatment cohorts was 10.3 months (95% CI: 9.5-11.2). A subset of overall survival estimates in the different treatment cohorts is shown in Table 1.

      Table 1. Select baseline patient characteristics and overall survival
      Baseline Patient Characteristics Overall Survival Estimates (unadjusted)
      Treatment Cohort[a] Age ≥70 Years (%) ECOG PS of 2/3 (%) Stage IV (%) Non-squamous Histology (%) All patients Median OS in Months (95% CI) Non-squamous Median OS in Months (95% CI) Non-squamous Cisplatin[b] Median OS in Months (95% CI)
      Pemetrexed + Platinum[b ](n=569) 23 18 86 97 10.7 (9.4-12.3) [n=569] 10.6 (9.4-12.0) [n=553] 11.6 (9.9-13.8) [n=374]
      Gemcitabine + Platinum[b] (n=360) 35 11 74 56 10.0 (8.4-11.8) [n=360] 8.4 (7.0-10.6) [n=201] 8.4 (6.7-10.8) [n=107]
      Taxanes + Platinum[b ](n=295) 36 23 75 64 9.1 (8.0-11.3) [n=295] 8.1 (7.4-10.1) [n=189] 9.6 (7.1-14.1) [n=44]
      Vinorelbine + Platinum[b] (n=300) 28 15 67 53 10.7 (8.9-12.8) [n=300] 10.1 (8.0-13.1) [n=160] 9.9 (7.2-13.4) [n=91]
      [a]A fifth cohort, the ‘other’ + platinum cohort contained a small number of subjects (n=40) and it was not included in the analyses presented here [b]Cisplatin is the platinum agent in the EMA approved prescription drug label

      Conclusion
      This observational study of first-line treatment for advanced NSCLC provides data describing patients and their survival outcomes in a real-world European practice setting between 2009 and 2012.

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      MO24.09 - DISCUSSANT (ID 3943)

      10:30 - 12:00  |  Author(s): E. Felip

      • Abstract
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      Abstract not provided

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      MO24.10 - Serum iron levels increased by cancer chemotherapy correlate the chemotherapy-induced nausea and vomiting (ID 2080)

      10:30 - 12:00  |  Author(s): T. Miya, S. Kuzu, K. Kamio, A. Gemma

      • Abstract
      • Presentation
      • Slides

      Background
      Despite the introduction of antiemetic treatments including corticosteroids, serotonin (5-HT3) receptor antagonists and neurokinin-1 receptor antagonist, chemotherapy-induced nausea and vomiting (CINV) remains major adverse toxicity of cancer chemotherapy deteriorating patient’s quality of life. It is recommended that these antiemetic treatments should be adopted according to the emetic risk classification of clinical practice guideline, however, the treatments are not so effective in delayed CINV comparing to acute CINV. The mechanism of delayed CINV is not clear so that effective antiemetic drug have not been developed yet. Iron poisoning in cases of blood transfusion or oversupply of iron supplement have various symptoms such as nausea, vomiting, gastroenteritis and liver injury caused by free radical iron, so-called Fenton reaction. We hypothesized that these symptoms are very similar to the adverse effects of cancer chemotherapy and that CINV may be related to the iron level of the patients receiving chemotherapy.

      Methods
      The patients with lung cancer received cytotoxic chemotherapy were included to this study if the serum level of iron, unsaturated iron binding capacity (UIBC ) and ferritin before the chemotherapy, on day 2, and day 8 were available. All chemotherapeutic regimens were administered as standard practice indicated by Japan governmental insurance. The treatment regimens were classified to highly emetogenic chemotherapy (HEC), moderately emetogenic chemotherapy (MEC) and low emetogenic chemotherapy (LEC) according to the clinical practice guideline of the American Society of Clinical Oncology to investigate the relationship between the change of serum iron level and CINV.

      Results
      A total of 37 patients (male26/femal11) were included. The number of patients of each classification were 18 in HEC (cisplatin+etoposide), 14 in MEC(caboplatin+gemcitabine, calboplatin+paclitaxel, calboplatin+etoposide, carboplatin+pemetrexed,irinotecan and amrubicin), 5 in LEC(pemetrexed). Serum iron level (μg/dl) of patients received HEC were 64.6±42.0 before treatment, 233.5±50.0 on day 2, and 235.5±41.3 on day 8. Those of MEC were 62.8±17.0 before treatment, 224.3±33.0 on day 2, and 175.7±87.6 on day 8. Those of LEC were 54.6±17.3 before treatment, 116.4±36.6 on day 2, and 40.7±33.5 on day 8. The serum iron levels of all patients markedly increased on day 2 and there were significant difference between LEC and the other two groups (p=0.01). The iron levels of LEC decreased to normal, on the contrary, those of other two groups remained abnormally high on day 8. With the increase of iron, the significant decrease of UIBC was observed implying that free radical iron appeared after the chemotherapy

      Conclusion
      Serum iron levels were closely correlated to CINV. This phenomenon may be a clue to new approach for antiemetic treatments.

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      MO24.11 - A prospective multicenter observational study of chemotherapy induced nausea and vomiting in lung cancer patients (ID 862)

      10:30 - 12:00  |  Author(s): K. Takayama, M. Fujita, A. Ono, K. Takeda, T. Ohira, H. Isobe, N. Ebi, K. Tateishi, N. Yamamoto, Y. Nakanishi, K. Tamura

      • Abstract
      • Presentation
      • Slides

      Background
      Chemotherapy-induced nausea and vomiting (CINV) is one of the major causes to deteriorate patient’s quality of life. Therefore, it is important to assess the current status of CINV nationwide for the appropriate treatment method to manage CINV. For this purpose, prospective multi-center observational study was performed in Japan.

      Methods
      Between 2011/Apr and 2012/Dec, 458 lung cancer patients who underwent systemic chemotherapy with high (HEC) or moderate emetogenic agents (MEC) were registered and the data in 429 patients were analyzed. CINV status was assessed in acute phase (within 24 hours from chemotherapy start) and late phase (after 24 hours) separately. Multivariate analysis was performed to clear the predictive factors in patient background for CINV.

      Results
      Patient background was as follows; median age 65, 318 male and 111 female patients, 190 patients treated with HEC and 239 with MEC. In acute phase, nausea and vomiting were observed in 5.6% (HEC 6.8%, MEC 4.6%) and 1.2 % (HEC 0.5%, MEC 1.7%) of all patients, respectively. In late phase, nausea and vomiting were observed in 40.1% (HEC 46.3%, MEC 35.2%) and 9.6 % (HEC 7.9%, MEC 10.9%) of all patients, respectively. The frequency of nausea in late phase is significantly higher in HEC than that in MEC. The predictive factors for nausea were a younger age in female patients, and younger age, no drinking history, decreased hemoglobin in male patients. The prediction of CINV by physician was relatively poor in late phase vomiting.

      Conclusion
      In this study, the current status of CINV and antiemetic therapy in lung cancer patients in Japan were elucidated. CINV was frequently observed in late phase and the appropriate management for late emesis is needed according to the guideline.

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      MO24.12 - Association between POLI polymorphism and severe gastrointestinal toxicity in non-small cell lung cancer patients in a Chinese population (ID 1087)

      10:30 - 12:00  |  Author(s): M. Shao, T. Chu, B. Han

      • Abstract
      • Presentation
      • Slides

      Background
      POLI is one of the Y-family polymerases, which are considered as error-prone replicases with low fidelity and involved in translesion synthesis (TLS) pathway. Polymorphisms on POLI genes may affect efficiency of DNA damage tolerant repair, therefore affect the platinum-based chemotherapy tolerance in tumor tissue and maintain routine function of normal organs. Our study aimed to investigate the association of five SNPs of POLI at codon 731, 5’-upstream and 3’UTR with prognosis and severe toxicity in advanced NSCLC patients in eastern developed regions in China.

      Methods
      663 stage III-IV aNSCLC patients treated with first-line platinum-based chemotherapy were genotyped with MassARRY platform on the five polymorphisms.

      Results
      p.731Ala (G of rs8305) indicated protective tendency from severe grade III-IV gastrointestinal toxicity in a dominant genetic model (adjusted odds ratio for Ala/Ala+Ala/Thr: 0.51, 95% confidence internal, 0.28-0.93; P for trend = 0.028). Stratified analysis revealed that the protective effect was rather for cisplatin- than carbonplatin-based regiments (adjusted OR for Ala/Ala+Ala/Thr: 0.38, 95% CI, 0.18-0.81; P for trend = 0.012). As linked loci of rs8305, rs3730668 on 5’-upstream and rs513543 on 3’-UTR of POLI performed similar protective tendency to gastrointestinal toxicity. No significant association was discovered for these five SNPs with other hematological toxicity, progress-free survival and overall survival. Both haplotype and diplotype analysis revealed consistent result as single polymorphism analysis. Haplotype “AAA” (in the order of rs3730668-rs8305-rs513543) indicated a significant susceptibility to gastrointestinal toxicity (adjusted OR: 1.92; 95% CI, 1.19-3.10; P = 0.007).

      Conclusion
      For the first time, our study indicated error-prone replicase POLI was associated with gastrointestinal toxicity in aNSCLC patients accepting first-line platinum-base chemotherapy, especially for cisplatin-based regiments.

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      MO24.13 - Volume based growth tumor kinetics as a predictive biomarker in patients with EGFR-mutant lung adenocarcinoma receiving EGFR tyrosine kinase inhibitor (ID 1229)

      10:30 - 12:00  |  Author(s): H.Y. Lee, M. Ahn, J. Kim, H. Kang, J.B. Seo, J.H. Lee

      • Abstract
      • Presentation
      • Slides

      Background
      To determine whether volumetric assessment has potential as a predictive biomarker and to assess relationship between longitudinal tumor data during treatment and prognosis in lung adenocarcinoma patients with sensitizing EGFR mutations treated with EGFR tyrosine kinase inhibitor (TKIs).

      Methods
      We retrospectively assessed patients with EGFR-mutant stage IV lung adenocarcinoma, who underwent EGFR TKIs as second-line therapy and this treatment was repeated every three weeks until disease progression. All 106 patients with at least one measurable lung lesions were quantitatively analyzed in terms of tumor size and volume based on the whole tumor volume, on baseline contrast-enhanced CT scans and on follow-up CT scans of every two treatment cycle. A quantify for tumor response was evaluated with growth tumor kinetics, followed by determining correlation with early tumor parameters including change of size, volume, and response rate. Cox-proportional hazard model and Log-rank test were also applied to predict the overall survival. Figure 1

      Results
      Percent of volume change after two cycles of TKI treatment had a strong correlation with progression rate based on growth tumor kinetics (P < 0.001). Responders based on percent of volume change after two cycles of TKI treatment had a higher overall survival rate than non-responders (P = 0.001). The velocity of progression was also a good potential parameter to predict overall survival (P < 0.001). Figure 1

      Conclusion
      Early radiologic parameters of the tumor helped predict treatment response and overall survival in EGFR mutant lung adenocarcinoma patients treated with TKIs. Longitudinal tumor data also showed potential as a predictive factor.

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      MO24.14 - DISCUSSANT (ID 3944)

      10:30 - 12:00  |  Author(s): K. O'Byrne

      • Abstract
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      Abstract not provided

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    O04 - Molecular Pathology I (ID 126)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 8
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      O04.01 - Identification of CD74-NRG1, a new recurrent fusion gene in invasive mucinous lung adenocarcinomas of never smokers (ID 4022)

      10:30 - 12:00  |  Author(s): L. Fernandez-Cuesta, D. Plenker, H. Osada, R. Sun, R. Menon, F. Leenders, M. Peifer, W. Vogel, I. Dahmen, G. Wright, P. Russell, Z. Wainer, B. Solomon, E. Brambilla, H.N. Mignotte, D. Moro-Sibilot, C.G. Brambilla, S. Lantuejoul, J. Altmüller, C. Becker, P. Nürnberg, J.M. Heuckmann, E. Stoelben, J.H. Clement, J. Sänger, M. Vingron, T. Zander, J. Wolf, S. Perner, S. Ansen, S.A. Haas, Y. Yatabe, R. Thomas

      • Abstract
      • Presentation
      • Slides

      Background
      Lung adenocarcinoma (AD) of patients who have never smoked frequently bear targetable genome kinase alterations, such as EGFR mutations and translocations affecting ALK, ROS1, and RET genes. These mutations correlate with kinase inhibitor sensitivity in mouse models or in patients. Unfortunately, therapeutically relevant kinase alterations are not present in all lung cancer specimens. Thus, additional genome alterations need to be discovered in order to provide a therapeutic opportunity for the remaining patients.

      Methods
      We collected a cohort of 25 AD specimens of never smokers lacking mutations in KRAS or EGFR, in which we performed transcriptome sequencing with the aim of identifying new oncogenic driver genes.

      Results
      We were able to identify known kinase fusions affecting ALK, ROS1 and RET genes in 3 cases each. Moreover, we detected one sample carrying a novel chimeric transcript fusing the first six exons of CD74 to the EGF-like domain of the NRG1 III-β3 isoform, leading to the expression of its EGF-like domain in an otherwise NRG1-negative tumor tissue. The fusion gene was further detected in four additional cases out of 94 pan-negative* ADs of never smokers. In total, all 5 cases were identified in stage I invasive mucinous lung adenocarcinomas (IMA) of never smoker females. This tumor type frequently presents with multifocal unresectable disease, for which no effective treatment has been yet established. IMA is highly associated with KRAS mutations; indeed, out of 15 IMA analysed, 6 carried a KRAS mutation (40%), and 4 the CD74-NRG1 fusion (27%). Given the fact that NRG1 signals through ERBB3 and ERBB4 receptors, we aimed to determine which receptor CD74-NRG1 provides the ligand for. We observed that ERBB4 was not expressed in the index case, while ERBB3 was relatively highly expressed and this expression also correlated with a positive phospho-ERBB3 (p-ERBB3) signal in the tumoral tissue of all 5 CD74-NRG1 positive cases. In order to test if this phosphorylation of ERBB3 was statistically significant, we stained a cohort of 241 ADs and found that p-ERBB3 was only positive in 6 of them (p-value<0.0001). Additionally, although both EGFR and ERBB2 were expressed in the index case, only ERBB2 expression correlated with a p-ERBB2 positive signal. These data suggest that CD74-NRG1 might provide the ligand for ERBB3, which may form heterodimers with ERBB2, since ERBB3 is devoid of intrinsic kinase activity and cannot support linear signaling in isolation. This is in line with previous studies showing that NRG1 induces an oncogenic signal through ERBB2-ERBB3 heterodimers engaging the PI3K-AKT pathway. This was further supported by the activation of the PI3K-AKT, but not the MAPK pathway, in CD74-NRG1 transduced H2052 lung cells, after 24h starvation. *pan-negative: EGFR, KRAS, ALK, HER2, BRAF, ROS1 and RET wild-type

      Conclusion
      Altogether, these data shows that CD74-NRG1 is a new recurrent oncogenic fusion gene, highly associated with IMA of never smokers. It also suggests that CD74-NRG1 fusion protein signals through the ERBB2-ERBB3 receptors complex leading to the activation of the PI3K-AKT pathway, providing a therapeutic opportunity for a tumor type with, so far, no effective treatment.

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      O04.02 - Using NGS for Mutational Profiling of NSCLC in the Clinical Setting (ID 2571)

      10:30 - 12:00  |  Author(s): S. Roy Chowdhuri, M. Routbort, K. Patel, R. Singh, R. Broaddus, A. Lazar, K. Aldape, R. Luthra, I.I. Wistuba, G.R. Simon

      • Abstract
      • Presentation
      • Slides

      Background
      Recent advances in molecular characterization of lung cancer have led to the identification of potential therapeutic targets that play key roles in regulating cell growth and proliferation. With the introduction of new targeted therapies, it becomes increasingly important to accurately characterize mutation status in lung cancer patients to provide personalized care that define prognosis and predict response to therapy. The advent of next generation sequencing (NGS) platforms in the realm of clinical molecular diagnostics has made multi-gene mutational profiling an affordable and highly successful methodology for massively parallel sequencing using small quantities of DNA.

      Methods
      Tumor specimens from 262 distinct samples of primary lung carcinoma including adenocarcinoma (n=228), squamous cell carcinoma (n=15), non small cell cancer not otherwise specified (NSC-NOS) (n=8), poorly differentiated carcinoma (n=4), neuroendocrine carcinoma (n=2), small cell carcinoma (n=1) and pleomorphic carcinoma (n=4) were tested by NGS. Tumor samples included formalin-fixed paraffin-embedded surgical core needle biopsies, resection specimens, cytopathology cell blocks, as well as cytopathology direct smears. Ten ng of DNA from each sample was tested for mutations in hotspot regions of 46 cancer related genes (Ion AmpliSeq Cancer Panel) using either a 316 chip or a 318 chip on an Ion Torrent Personal Genome Machine (PGM) Sequencer (Life Technologies, CA).

      Results
      Mutations were detected in 222/240 (93%) patients with a histologic diagnosis of adenocarcinoma, NSC-NOS or PDC. EGFR mutations were detected in 47 (20%) of these patients and double EGFR mutations identified in 13 cases, including acquired resistance mutations T790M (n=6) and S768I (n=3). KRAS mutations were detected in 61 (25%) cases, most commonly involving codons 12 and 13 (n= 58) and less frequently involving codons 61 and 146 (n= 3). TP53 was most frequently mutated (n=65; 27%) and was often seen in conjunction with EGFR mutations (n=14; 5%) and KRAS mutations (n=15; 6%). Mutations were detected in 10/15 (67%) squamous cell carcinomas with mutations in TP53 (n=5), CDKN2A (n=3) and PIK3CA (n=2) most frequently seen. Additional mutations detected at a lower frequency from the entire dataset were STK11, ATM, BRAF, PIK3CA, CTNNB1, IDH1, NRAS, CDKN2A, KDR, RET, MET, FBXW7, APC, RB1, FLT3, GNAS, ABL1, HRAS, PTPN11, JAK3, NOTCH1, SMAD4, SMARCB1, SMO, MLH1, AKT1, and ERBB4.

      Conclusion
      In summary, our results show that NGS-based mutational profiling using small amounts of DNA derived from FFPE as well as cytology smears can provide important information regarding mutation status of genes that play key roles in growth and progression of tumor in lung cancer patients and can provide insight into directing personalized cancer therapy.

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      O04.03 - Oncogene Mutations and Novel Transcript Fusions in Lung Adenocarcinoma from Never Smokers (ID 2939)

      10:30 - 12:00  |  Author(s): J. Jen, J.S. Jang, A. Lee, J. Li, Y. Asmann, M. Erickson-Johnson, A.O. Bungum, V. Simon, E.S. Edell, K.J. Kopp, B. Eckloff, A. Oliveira, E. Wieben, M.C. Aubry, E. Yi, D.A. Wigle, P. Yang, R.B. Diasio

      • Abstract
      • Presentation
      • Slides

      Background
      Lung adenocarcinoma from never smoker represents a unique disease entity in that they often involve females of younger age and have a distinct mutation spectrum compared to those of smoker population. Mutations from the tumors of these patients often involve oncogenes that can be targeted for therapy by small molecule kinase inhibitors. We surveyed for tumor specific genetic changes in lung adenocarcinomas from never smokers for common oncogene mutations and transcript fusions.

      Methods
      We first developed a multiplex assay detecting187 mutations in 10 actionable oncogenes frequently affected in lung cancer. We used this assay to examine 89 lung adenocarcinomas from never smokers identified through the Mayo Clinic Epidemiology and Genetics of Lung Cancer Program. NextGen sequencing (RNASeq) was used to identify transcript fusions affecting either a known kinase or an oncogene in 20 of 89 tumors. RT-PCR, FISH and IHC were used to verify the novel fusion identified in this study.

      Results
      Sixty-four tumors had mutation in at least one of the tested oncogenes involving EGFR (49 cases, 55%), k-RAS (5 cases, 6%), MET (9 cases, 10%), BRAF (4 cases, 5%), PIK3CA (2 cases, 2%), and ERBB2 (4 cases, 5%). RNAseq identified five transcript fusions among the 20 tested tumors, involving known fusions of EZR- ROS1 or KIF5B-RET and three novel fusions involving SND1-BRAF, EML4-BIRC6, and GMEB2-TERT genes. We used RT-PCR to confirm the presence of the SND1-BRAF fusion transcript that involved exons 1-9 of SND1 with exon 2 to 3’ end of the BRAF on chromosome 7. Screening all 89 tumors by RT-PCR identified a total of three tumors with the identical fusion. Interestingly, two of these three tumors with a BRAF fusion also had a concurrent mutation in EGFR gene (S768I) and a third tumor had an additional mutation in the ERBB2 gene (M774_A775ins). Four additional samples were positive for EML4-ALK fusion by IHC and FISH.

      Conclusion
      In our study of a primarily Caucasian population, a majority of lung adenocarcinomas from never smokers (70/89, or 78.6%) carry at least one genetic mutation in a targetable gene. For the first time, we report the presence of a transcript fusion involving SND1-BRAF in lung adenocarcinoma and that these fusions are present in tumors also having EGFR or ERBB2 mutations. Combined together, activation of BRAF by either point mutation or transcript fusion is one of the most frequent events in our study accounting for 7/89 (8%) cases. These findings support a rapid and targeted gene mutation testing strategy for lung adenocarcinoma from never smokers, as the knowledge of these mutations can be readily used to augment therapeutic management.

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      O04.04 - DISCUSSANT (ID 3982)

      10:30 - 12:00  |  Author(s): I.I. Wistuba

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      O04.05 - Epidemiology of PI3K pathway alterations in patients with metastatic non-small cell lung cancer (NSCLC): findings from the international BASALT-1 study (ID 1810)

      10:30 - 12:00  |  Author(s): G.K. Dy, J. Vansteenkiste, M. Thomas, T. De Pas, F. Grossi, J. De Grève, E. Felip, J. Canon, J. Gray, F. De Braud, M. Reck, S. Thongprasert, D. Planchard, C. Gridelli, P. Roussou, M. Gurnani, G. Atalla, D.W. Sternberg, J.A. Engelman

      • Abstract
      • Presentation
      • Slides

      Background
      Buparlisib (BKM120) is an oral PI3K inhibitor that inhibits all four isoforms of class I PI3K (α, β, γ, δ) and has demonstrated antiproliferative, proapoptotic, and antiangiogenic activity in multiple preclinical cancer models. NSCLC cell lines with PIK3CA mutations (muts) have demonstrated increased sensitivity to buparlisib in vitro. BASALT-1 – an ongoing, multicenter, open-label, two-stage Phase ll study (NCT01297491) – evaluates the safety and efficacy of single-agent buparlisib in patients (pts) with NSCLC and an activated PI3K pathway. Here we report data on the prevalence of PI3K pathway alterations in pts with squamous (sq) or non-squamous (non-sq) NSCLC prescreened for entry into BASALT-1.

      Methods
      Pts prescreened for BASALT-1 were ≥18 years of age with previously treated metastatic NSCLC of sq or non-sq histology. PI3K pathway activation (defined as PIK3CA mut and/or PTEN mut and/or PTEN negative [neg; <10% protein expression at 1+ by immunohistochemistry]) was measured in archival or newly acquired tumor tissue collected at prescreening. PIK3CA (exons 1, 5, 7, 9, and 20) and PTEN (exons 1–9) muts were detected primarily using Sanger sequencing in a centralized fashion. Local analysis was permitted at selected sites where a SnapShot approach was most commonly used.

      Results
      As of April 10, 2013, 1183 pts had submitted tumor samples to be assayed (1179 tumors had known histology). PI3K pathway activation was detected in 16.0% of sq and 11.3% of non-sq tumors. In sq tumors (N=612), loss of PTEN protein expression (8.2%) was the most common single alteration observed, followed by PIK3CA mut only (3.1%) and PTEN mut only (2.9%). In non-sq tumors (N=567), PTEN mut only was the most common alteration (4.9%), followed by PIK3CA mut only (2.6%) and PTEN neg only (2.1%). Frequencies of co-existing genetic alterations were: PTEN mut + PTEN neg only (1.0% sq vs 0.4% non-sq), PIK3CA mut + PTEN neg only (0.7% sq vs 0.4% non-sq), PIK3CA mut + PTEN mut only (0% sq vs 0.9% non-sq), and PIK3CA mut + PTEN mut + PTEN neg (0.2% sq vs 0% non-sq). No clear gender, age or ethnicity effects were observed (Table). Figure 1

      Conclusion
      The findings from our large dataset indicate that genetic alterations in the PI3K pathway occur in a clinically significant proportion of pts with sq and non-sq relapsed NSCLC. An accurate characterization of PI3K pathway alteration frequencies in NSCLC will help guide the design of future clinical trials of PI3K inhibitors.

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      O04.06 - An international standardization study using the ALK IHC antibody D5F3 and a sensitive detection kit demonstrates high concordance between ALK IHC and ALK FISH and between evaluators (ID 2875)

      10:30 - 12:00  |  Author(s): M.W. Wynes, M. Dietel, E. Schuuring, L.M. Sholl, M. Tsao, Y. Yatabe, R.R. Tubbs, F. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background
      The goal of personalized medicine is treating patients with a therapy predicted to be efficacious based on the molecular characteristics of the tumor, thereby sparing the patient futile or detrimental therapy. Anaplastic lymphoma kinase (ALK) inhibitors are effective against ALK positive non-small cell lung cancer (NSCLC) tumors, but to date the only US Food and Drug Administration approved companion diagnostic is a break-apart fluorescence in situ hybridization (FISH) assay. Immunohistochemistry (IHC) is a clinically applicable cost-effective test that is sensitive and specific for ALK protein expression. The purpose of this study was to assemble an international team of expert pathologists to evaluate and standardize the interpretation of a new automated standardized ALK IHC assay.

      Methods
      Archival NSCLC tumor specimens (n=103) previously tested for ALK rearrangement by FISH were provided by the international collaborators. These specimens were stained by IHC with the anti-ALK (D5F3) primary antibody (Ventana Medical Systems, Inc) combined with OptiView DAB IHC detection and OptiView amplification (Ventana Medical Systems, Inc). The evaluators went through an interpretation training session and scored the specimens as positive, if strong granular cytoplasmic brown staining was present in tumor cells, or negative. IHC results were compared to the FISH results and inter-evaluator agreement comparisons made.

      Results
      Overall for the 100 evaluable cases the ALK IHC assay was highly sensitive (90%), specific (95%) and accurate (93%) relative to the ALK FISH results. Similar results were observed using a majority score. For the discrepant cases IHC negativity was scored by 7/7 on 3 FISH positive cases and 6/7 evaluators on 2 additional FISH positive cases. IHC positivity was scored on 2 FISH negative cases by 7/7 readers. There was agreement among 7/7 and 6/7 readers on 88% and 96%% of the cases before a consensus review, respectively, and following a review there was agreement among 7/7 and 6/7 on 95% and 97% of the cases, respectively.

      Conclusion
      Based on expert evaluation the ALK IHC assay using the D5F3 antibody combined with Optiview Detction and Optiview amplification is sensitive, specific and accurate, relative to FISH, and a majority score of multiple readers does not improve these results over an individual reader’s score. Excellent inter-reader agreement was observed for the IHC assay. These data support the algorithmic use of ALK IHC as a screening procedure for ALK protein expression in NSCLC.

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      O04.07 - Distinguish synchronous multiple primary lung cancers from intrapulmonary metastasis by genome sequencing (ID 3193)

      10:30 - 12:00  |  Author(s): Y. Liu, L. Li, G. Yin, D. Lin, X. Liu, Y. Gao

      • Abstract
      • Presentation
      • Slides

      Background
      Owing to use of high-resolution computed tomography (CT) scan for lung cancers, small nodules could be detected, so that more patients are identified carrying more than one lesion in lung synchronously at the time of diagnosis. Under this circumstance, precisely distinguish multiple primary lung cancers from intrapulmonary metastasis has important significance on clinical staging and appropriate therapy design.

      Methods
      We comprehensively compared genomic aberration profiles of each tumor in the patients with multifocal pulmonary lesions, assuming that metastasis shared a certain portion of genetic aberrations with the lesion it was originated. Therefore, whole-genome/exome sequencing were applied on 15 intrapulmonary tumors that had highly similar histological diagnosis, and 1 lymph node metastasis derived from six patients with synchronous multifocal lung cancers. The somatic nucleotide variations (SNVs) detected by whole-genome/exome sequencing were validated by either mass spectrometry or the Sanger sequencing.

      Results
      A total of 344 non-synonymous somatic point mutations were detected in whole genome sequencing analysis (3 lesions and 1 lymph node metastasis in 1 patient), corresponding to 306 unique mutation sites. Among the 70 mutations detected in the lymph node metastasis, 36 (51.4%) were also found in lesion 1 of the 3 intrapulmonary lesions, whereas no shared mutation were detected between the metastasis and either of the other two lesions. Meanwhile, there was only 1 common mutation between lesion 2 and 3, while no shared mutations were observed between lesion 1 and 2 or lesion 1 and 3. These results suggested that the metastasis was originated from lesion 1 and the 3 lesions were independent primary tumors. In whole exome sequencing analysis (12 lesions from 5 patient), among the 389 somatic non-synonymous mutations detected, we observed a similarity between each pair of tumors within one patient ranged from 0% to 5.3%, suggesting that all the lesions were independent primary tumors rather than intrapulmonary metastasis. We also reached a same conclusion when we included all somatic mutations found across the genome/exome in the analysis. These genomic abnormality profile-based diagnosis were consistent with the diagnosis based on histological examination except one lesion in patient 5, which had been considered as an intrapulmonary metastasis by histological judgment. At the same time, EGFR or KRAS mutations, which are therapy targets for adenocarcinoma in lung were detected in 7 or 3 out of the 15 tumors in 3 or 2 patients, respectively. Heterogeneity was also observed in mutation status of these two genes among different lesions in a single patient.

      Conclusion
      Comprehensive genomic aberration profiling is powerful for identification of multiple primary lung cancers. The lymph node metastasis in the study stands as a positive control, compared with which we could tell that lesions from multifocal primary lung cancers shared too few somatic mutations to be intrapulmonary metastasis. Considering the heterogeneous mutation status of EGFR or KRAS among different tumors derived from a single patient with multifocal primary lung cancer, molecular diagnosis should be taken for each accessible lesion when targeted adjuvant therapy is under consideration.

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      O04.08 - DISCUSSANT (ID 3983)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    O14 - Radiotherapy - Toxicity and Clinical Trials (ID 105)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 8
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      O14.01 - Memory preservation with conformal avoidance of the hippocampus during whole-brain radiotherapy for patients with brain metastases: Preliminary results of RTOG 0933 (ID 2262)

      10:30 - 12:00  |  Author(s): V. Gondi, M.P. Mehta, S. Pugh, W.A. Tome, B. Corn, C. Caine, A. Kanner, H. Rowley, V. Kundapur, J.N. Greenspoon, A.A. Konski, G.S. Bauman, W. Shi, V. Kavadi, L. Kachnic

      • Abstract
      • Presentation
      • Slides

      Background
      Preclinical and clinical evidence suggests that hippocampal dose during whole-brain radiotherapy (WBRT) plays a role in cognitive decline. This may be preventable by conformally avoiding the hippocampus during WBRT (HA-WBRT). RTOG 0933 was a single-arm phase II study of HA-WBRT for brain metastases with cognitive function assessments and pre-specified comparison to a historical control of WBRT without hippocampal avoidance.

      Methods
      Eligible adult patients with brain metastases received HA-WBRT to 30 Gy in 10 fractions. Standardized cognitive function assessments were performed at baseline, 2, 4, and 6 months. The primary endpoint was change in the Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-DR) at 4 months. The historical control consisted of brain metastases patients treated with WBRT on the PCI-P-120-9801 phase III trial, which demonstrated a 30% mean relative loss in HVLT-DR from baseline to 4 months. To detect a minimum relative 50% improvement in this end-point, leading to an absolute 15% or less mean relative loss in HVLT-DR following HA-WBRT, 51 analyzable patients were required to ensure 80% statistical power with a one-sided alpha=0.05.

      Results
      113 patients were accrued from April 2011-November 2012; 56 out of 100 eligible patients had non-small cell lung cancer (NSCLC). One grade 3 toxicity of cerebral edema and no grade 4 or higher toxicities were reported. Median survival was 6.9 months (95% confidence interval (95% CI) 4.8-15.2 months). 41 patients were analyzable at 4 months. Mean relative change in HVLT-DR from baseline to 4 months was +3.3% (95%CI: -8.0% to +14.6%), which was significant in comparison to the historical control (p<0.0001) and substantially exceeded the hypothesized -15% value. 28 patients were analyzable at 6 months with a mean relative change in HVLT-DR from baseline to 6 months of +4.6% (95%CI: -8.6% to +17.8%), a finding in dramatic contrast to expected continued deterioration in HVLT-DR scores from other WBRT trials. In terms of patients with NSCLC, 21 patients were analyzable at 4 months, with a mean relative change in HVLT-DR from baseline to 4 months of +10.0% (95%CI: -9.5% to +27.1%). At 6 months, 14 patients with NSCLC were analyzable, with a mean relative change in HVLT-DR from baseline to 6 months of 0.0% (95%CI: -18.5% to +18.5%).

      Conclusion
      Conformal avoidance of the hippocampus during WBRT is associated with memory preservation at 4 and 6 months follow-up in NSCLC patients, who comprised the majority of accrued and analyzable patients on this trial. These promising phase II results warrant further validation in a phase III trial, currently under development in the RTOG.

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      O14.02 - Vertebral fractures in NSCLC patients treated with IMRT and concurrent chemotherapy (ID 1880)

      10:30 - 12:00  |  Author(s): W. Uyterlinde, C. Chen, J.J. Sonke, J. De Bois, J. Belderbos, M. Van Den Heuvel

      • Abstract
      • Presentation
      • Slides

      Background
      Purpose To report on the incidence of vertebral fractures in locally advanced NSCLC patients treated with intensity modulated radiation therapy (IMRT) and concurrent chemotherapy. The RT dose to the vertebra was analyzed for its association with fractures.

      Methods
      Methods A total of 524 patients were treated between 2007 and 2011, with hypofractionated IMRT (66Gy/24fx) and concurrent daily low dose cisplatin. Planning and follow-up CT or MRI scans were retrospectively utilized to identify vertebral collapse by an experienced radiologist and a technician. Clinical and dosimetric parameters were retrospectively collected. Patients were excluded if they had no follow-up CT/MRI scan; had prior irradiation for thoracic or head and neck cancer; showed a vertebral fracture in the planning CT; or had vertebral collapse due to other causes. First, we reported the incidence of vertebral fractures. Afterwards, we analyzed the RT dose effect relationship using the maximum (Dmax) and mean (Dmean) dose to each vertebra. Dose-response was modeled using Cox model with patient as random effect. Data were analyzed using R, package “coxme”.

      Results
      Results Three hundred and thirty six patients were eligible for analysis. The median follow-up was 24 months The median age was 64 years (range 32-87); 40% of the patients female and 94% had a performance score (PS) 0-1. Twenty-eight (8%) patients developed ≥ 1 vertebral fracture; 22 had 1 vertebral fracture, 5 had 2 and 1 patient had 3 vertebral fractures. All fractures were located from the 6[th]-8[th] thoracic vertebra.The median onset time for the fracture was 7 months (range 2-26). The median age for the 28 fractured patients was 70 years (range 42-82); 61% were female, 89% had a PS of 0-1. The median Dmax was 40Gy (range 0-83) and 72Gy (range 42-83) for non-collapsed and fractured vertebrae, respectively. The median Dmean was 12Gy (range 0-65) and 51Gy (range 18-71) for non-collapsed and collapsed vertebras, respectively. Both Dmax and Dmean were significantly (p<0.001) associated with vertebral fractures.

      Conclusion
      Conclusion Vertebral fractures were retrospectively identified in 8% of NSCLC patients treated with IMRT and concurrent chemotherapy. The median onset time was 7 months. Both Dmax and Dmean of the vertebra were significantly associated with collapse in the collapsed population. A case-control study is in progress to analyze the dose-response relationship in the entire population and incorporate clinical variables, such as age, performance status and menopause status.

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      O14.03 - Using generalized equivalent uniform dose (gEUD) to model volume effects for brachial plexopathy after high-dose stereotactic body radiation therapy (SBRT) (ID 2835)

      10:30 - 12:00  |  Author(s): S.U. Din, E.L. Williams, Y. Yamada, E. Yorke, A. Foster, E. Poppens, A.J. Wu, A. Jackson, A. Rimner

      • Abstract
      • Presentation
      • Slides

      Background
      Brachial plexopathy is a rare but important toxicity of radiation therapy because of its significant impact on quality of life. For standard fractionated raiation therapy, good models of brachial plexus (BP) tolerance exist. However, the tolerance of the BP to SBRT is not well understood. We combined data from SBRT for apical lung and metastatic lesions near the BP spanning a wide range of doses and hypofractionation schemes. We determined the clinical incidence of brachial plexopathy and modeled the correlation with generalized equivalent uniform dose (gEUD) for both physical and biologically effective doses (BED) using a range of fractionation-sensitivity parameters (α/β) and volume effect parameters (a).

      Methods
      Between 2004 and 2012, 180 lesions (76 lung lesions and 104 metastatic lesions) located above the aortic arch and below the level of C3 were treated with SBRT. Patients with prior radiation therapy to this region were excluded. Metastases were treated to 14-30 Gy in 1-5 fractions and lung tumors to 22-60 Gy in 1-5 fractions. The BP was contoured per RTOG atlas definitions. For 54 centrally located spine metastases, both left and right BP were contoured and analyzed separately for a total of 234 BPs in 180 patients. Brachial plexopathy of ≥grade 1 (CTCAE v4.0) was the primary endpoint. Maximum dose to the BP (Dmax), minimum dose to the hottest 5% of the BP (D05), and their respective BEDs were calculated using α/β= 3 Gy. The gEUD was also calculated with the volume effect parameter (a) ranging from log~10~a= -1.0 to +1.0 in log~10~a steps of 0.1. A logistic regression model (LR) was fit to the data as a function of a. Clinical dose recommendations were derived with logrank tests using median splits.

      Results
      With median follow-up of 15.1 months, brachial plexopathy due to SBRT occurred in 9/234 BPs. Severity of brachial plexopathy was grade 1 in two, grade 2 in five and grade 3 in two patients. Median time to onset of brachial plexopathy was 6.2 months and the 1-/2-year actuarial rates were 3.3%/5.6%. For all patients the median BED for BP Dmax was 117.5 Gy and for D05 was 89.3 Gy. Median BED Dmax for patients with and without brachial plexopathy was 234 Gy and 115.2 Gy respectively (p=0.002). Brachial plexopathy was significantly associated with BP BED Dmax (p=0.002), and D05 (p=0.015), but not with physical dose. Using LR, the strongest correlation of gEUD with brachial plexopathy occurred for log~10~a= 1.0 using BED (p=0.002), which is representative of the BED Dmax. LR models of BED Dmax versus brachial plexopathy for various α/β values showed that any α/β<25 was a significantly better predictor than physical dose.

      Conclusion
      Brachial plexopathy is significantly associated with BED Dmax ≥117.5 Gy (equivalent to a physical dose of 17 Gy x1, 9.3 Gy x3 or 7 Gy x5 fractions) and D05 ≥89.3 Gy. BED Dmax was the most important predictor of this rare but serious toxicity.

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      O14.04 - DISCUSSANT (ID 3931)

      10:30 - 12:00  |  Author(s): F. Mornex

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      O14.05 - Effect of Postoperative 3D-Conformal Radiotherapy (3DCRT) for Patients with pIIIA-N2 non-small-cell lung cancer (NSCLC) after Complete Resection and Adjuvant Chemotherapy: Interim Analysis of a Prospective Phase III Study (ID 2299)

      10:30 - 12:00  |  Author(s): Z. Hui, J. Liang, J. Lv, X. Wang, Z. Zhou, Q. Feng, Z. Xiao, D. Chen, H. Zhang, W. Yin, L. Wang

      • Abstract
      • Presentation
      • Slides

      Background
      For patients with completely resected pⅢA-N2 NSCLC, the role of postoperative radiotherapy (PORT) is not well defined. 3D-conformal radiotherapy (3DCRT) can deliver high dose to the target volume while decreasing the toxicity of normal tissues, which may improve the treatment outcomes. This interim analysis of our phase III randomized clinical trial (NCT00880971) is to evaluate the effect of postoperative 3DCRT on the overall survival (OS) and failure pattern in pⅢA-N2 NSCLC patients after complete resection and adjuvant chemotherapy.

      Methods
      Between Jan. 2009 and May 2012, 128 consecutive patients with pⅢA-N2 NSCLC, after complete resection and four courses of platinum based chemotherapy, were randomized into PORT group or control group. Only patients who had finished the first follow-up 3 months after treatment were included in this interim analysis. PORT, using 3D conformal techniques, was 60 Gy by 30 fractions to the subcarinal nodes, ipsilateral mediastinum and ipsilateral hilum. The effect of PORT on survival was evaluated with Kaplan-Meier method and log-rank test. The treatment failure pattern was also analyzed. Pearson chi-Square test was used to compare the constituent ratios in different groups.

      Results
      Totally 96 patients were analyzed, including 49 in the PORT group and 47 in the control group. The clinical features were comparable between the two groups. For all the patients, the 3-y OS, disease free survival (DFS), loco-regional recurrence free survival (LRFS) and distant metastasis free survival (DMFS) were 68.4%, 54.6%, 68.6% and 63.0%, respectively. The survival rates of patients in the PORT and control groups are listed in the table. PORT markedly increased the 3-y OS, DFS, LRFS and DMFS by 21.6%, 18.7%, 16.4% and 20.4%, respectively. But the difference was not statistically significant due to the limited samples. There were 33 patients (34.3%) with treatment failure, including 7 (7.3%) with loco-regional recurrence only, 13 (13.5%) with distant metastasis only, and 13 (13.5%) with the both. PORT markedly decreased the loco-regional recurrence from 27.7% to 14.3% (P=0.107), but not the distant metastasis (from 29.8% to 24.5%, P=0.559). Eight deaths were observed up to the last follow-up, which were all caused by cancer progression. No death caused by radiation toxicities was observed.

      All Patients (n=96) PORT Group (n=49) Control Group (n=47) P Value*
      OS 68.4% 80.8% 59.2% 0.432
      DFS 54.6% 64.2% 45.5% 0.256
      LRFS 68.6% 76.4% 60.0% 0.105
      DMFS 63.0% 67.1% 46.7% 0.542
      *Between PORT and control groups.

      Conclusion
      For pⅢA-N2 NSCLC patients after complete resection and adjuvant chemotherapy, postoperative 3DCRT can markedly improve the survival and loco-regional control. Further accumulation of patients in our prospective randomized study is warranted.

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      O14.06 - Investigation of a Patient Reported Outcome (PRO) tool to assess radiotherapy-related toxicity in patients with lung cancer (ID 1614)

      10:30 - 12:00  |  Author(s): M. Christodoulou, P. McCloskey, N. Stones, N. Bayman, P. Burt, A. Chittalia, M. Harris, L.W. Lee, L. Pemberton, H. Sheikh, R. Swindell, C. Faivre-Finn

      • Abstract
      • Presentation
      • Slides

      Background
      Discrepancies between clinician and patient reported symptoms validate the investigation of a PRO tool in clinical trials and routine practice. There is a paucity of data regarding the feasibility and relevance of PRO tools to assess radiotherapy toxicity in patients with lung cancer.

      Methods
      From January to June 2013, lung cancer patients undergoing thoracic radiotherapy or chemo-radiotherapy completed a PRO toxicity tool (adapted Radiogenomics Biorepository and Databank lung questionnaire) consisting of 9 patient-adapted Common Terminology Criteria for Adverse Events (CTCAE) items and World Health Organisation (WHO) performance status (PS) at baseline, at the end of radiotherapy and at 4-10 weeks follow-up (FU). At the same time points, patients completed the European Organisation for Research and Treatment of Cancer Quality of Life (QoL) Questionnaire along with its lung cancer specific module (EORTC QLQ-C30/LC13) and the Hospital Anxiety and Depression Scale (HADS). Clinicians completed the same CTCAE items for each time point. Agreement between patients’ and clinicians’ toxicity reports was assessed using weighted kappa coefficients. The patients’ QoL and HADS scores were correlated with the patients’ and clinicians’ reported toxicity using Spearman rank correlation coefficients.

      Results
      Of the 116 patients consented, 70 (85 paired responses) completed all 3 questionnaires for at least one time point excluding baseline. Median age was 71.5 years (39-89 years), 54.3% of the patients were male and 85.7% had a diagnosis of non-small cell lung cancer. Agreement between patients’ and clinicians’ reported toxicity ranged from poor to substantial (Figure 1). Perfect agreement was ≥50% for all assessed items with the exception of PS for both the end of radiotherapy and FU. The majority of discrepancies (≥74%) differed by 1 grade of toxicity. At the end of radiotherapy patients reported greater severity than clinicians for all items but not for PS; however this was less pronounced at FU. QoL scores were generally more strongly correlated with the patients’ compared to clinicians’ matching toxicity grades at the exception of dyspnoea. The correlation of HADS scores with patients’ CTCAE anxiety and depression grades ranged from moderate-to-low to moderate. There was no correlation with clinicians’ grading for depression and no-to-moderate correlation for anxiety. The adapted Radiogenomics Biorepository and Databank lung questionnaire demonstrated a high Cronbach’s α value (0.848) indicating good reliability. Figure 1

      Conclusion
      The use of a PRO tool in radiotherapy for lung cancer is feasible, reliable and acceptable to patients and complements the clinicians’ assessment. Further research is required to evaluate its validity.

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      O14.07 - IDEAL CRT: Isotoxic Dose Escalation and Acceleration in Lung Cancer ChemoRadiotherapy - a phase I/II trial of concurrent chemoradiation with dose-escalated radiotherapy in patients with stage II or stage III Non-Small Cell Lung Cancer. (ID 1368)

      10:30 - 12:00  |  Author(s): D.B. Landau, I. Khan, Y. Ngai, L.L. Hughes, E. Miles, D. Wilkinson, E. Parsons, P. Mayles, H. Mayles, A.T. Bates, N. Mohammed, J. Hicks, S. Harden, M. Illsley, A. Garcia, Z. Malik, S. Hughes, J. Spicer, A. Baker, P. Wells, V. Laurence, J. Fenwick

      • Abstract
      • Presentation
      • Slides

      Background
      The IDEAL-CRT trial uses an individual patient approach to radiotherapy (RT) dose escalation, escalating the dose within a fixed overall treatment time, 6 weeks, by increasing dose per fraction. Isotoxic RT is based on the calculated risk of RT-pneumonitis (RTPN), RT dose being escalated so that all patients are exposed to the same RTPN risk. We investigated the feasibility and safety of individualised, isotoxic dose escalation for once daily RT delivered in 30 once-daily fractions with concurrent chemotherapy.

      Methods
      Eligibility; NSCLC stage II/III, PS 0/1, FEV~1~ (≥40% predicted or ≥1L), DCLO (≥40% predicted). A radiobiological model was used to individualize RT dose-prescription – selecting a dose which, in 30# once daily for 6 weeks, is associated with a 10% risk of grade 3+ RTPN, but limiting prescribed doses to between 63Gy - 73Gy (2Gy dose equivalent α:β=10, 63.5Gy-86Gy). Dose constraints were fixed for spinal cord, heart, brachial plexus. In Arm 1, initially the maximum dose to 1cc oesophageal did not exceed 63Gy. Arm 2 comprised patients in whom oesophageal dose rather than lung dose limited the prescription dose: the oesophageal dose was raised from 65Gy to 68Gy, 71Gy and 73Gy in consecutive cohorts, the prescribed dose lying between 63Gy and 73Gy and being the highest consistent with the oesophageal limit. Dose escalation was determined using a 6+6 design. Dose limiting toxicity (DLT) was defined as Grade 3+ oesophagitis. MTD was determined if grade 3+ oesophagitis >42% (>5/12). Two cycles of Cisplatin-Vinorelbine chemotherapy given concurrently during RT. All contouring and dosimetry on planning CT scans was centrally reviewed. IMRT was introduced in November 2012. Primary endpoints: oesophagitis and RTPN. Serial pulmonary function tests and ECGs performed. Efficacy endpoints: overall survival (OS), progression free survival (PFS), and tumour response.

      Results
      Between October 2010 and February 2013, 84 patients recruited (9 UK centres), 49 patients Arm 1, 35 patients Arm 2 (13 at 65Gy, 12 at 68Gy, 10 at 71Gy; none at 73Gy as the 73Gy upper prescription dose limit was only rarely associated with an oesophageal dose higher than 71Gy). Median follow up was 11 months (range 2,24); median age 66 years (range 43-84); 74% male; 39%/60% WHO 0/1; 30% adenocarcinoma, 54% squamous. Mean GTV 121cc (range 14-602cc). Mean prescribed dose for patients completing RT (n=80) 67.6Gy (range 63-73Gy) in Arm 1 and 70.1 Gy (63-73) in Arm 2. Mean 1cc-oesophageal-dose in Arm 1 55.5Gy (range 14.2-68.0Gy). In Arm 1 grade 3+ oesophagitis was 6% (3/49). In Arm 2, Grade 3+ oesophagitis was 17% (2/12) at 68Gy; no Grade 3+ oesophagitis in 65Gy (0/12) and 71Gy (0/10) cohorts. Grade 3+ RTPN 2% (1/49) in Arm 1 and 6% (2/35) in Arm 2. 1 year OS and PFS rates were 92% and 74% respectively.

      Conclusion
      Isotoxic RT dose escalation was safe and feasible. The MTD for oesophagus was not reached. Acceleration of the IDEAL-CRT schedule to five weeks is under investigation in a second study, currently recruiting.

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      O14.08 - DISCUSSANT (ID 3932)

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

      • Abstract
      • Presentation
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      Abstract not provided

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