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W. Klepetko
Moderator of
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SC16 - Superior Sulcus Tumors (ID 340)
- Event: WCLC 2016
- Type: Science Session
- Track: Radiology/Staging/Screening
- Presentations: 4
- Moderators:D. Jones, W. Klepetko
- Coordinates: 12/06/2016, 14:30 - 15:45, Lehar 1-2
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SC16.01 - Imaging Techniques for Staging and Restaging of Superior Sulcus Tumors (ID 6663)
14:30 - 14:50 | Author(s): H. Prosch
- Abstract
Abstract not provided
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SC16.02 - Surgical Approaches in Superior Sulcus Tumors (ID 6664)
14:50 - 15:10 | Author(s): D. Grunenwald
- Abstract
- Presentation
Abstract not provided
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SC16.03 - Radiotherapy for Sulcus Superior Tumors (ID 6665)
15:10 - 15:30 | Author(s): M. Werner-Wasik
- Abstract
- Presentation
Abstract:
Superior sulcus tumors (SST) are unique among lung cancer in that they have a tendency for the invasion into the chest wall and a spread superiorly outside the lungs, namely into the brachial plexus and the sympathetic chain, therefore causing a well-defined constellation of symptoms and signs, such as chest wall/arm/shoulder pain, Horner’s syndrome, spinal cord compression, upper extremity edema etc. A primary surgical resection is rarely performed, and bi- or trimodality therapies are most often implemented, depending on tumor stage. A comprehensive evaluation of the tumor extent is mandatory before any intervention is undertaken. Following tumor biopsy to establish a diagnosis of non-small cell lung cancer, standard lung cancer staging studies need to be obtained, such as the chest and upper abdomen computerized tomography (CT) scan with intravenous contrast, a PET CT scan and contrast-enhanced brain imaging (CT or MRI). Routine blood work and pulmonary function testing are standard as well. However, there are two additional radiographic studies which are necessary for each superior sulcus tumors: (1) MRI scan of the brachial plexus; (2) MRI scan of the cervical and thoracic spine. The rationale for imaging of the brachial plexus is not to confirm that the plexus is invaded (which is evident based on the presenting symptoms and a physical examination), but rather to assess the degree of its vertical involvement, since only the lowest trunks of the brachial plexus can be safely resected without fear of causing paralysis of the upper extremity. The MRI of the vertebral column serves a double purpose: (1) to assess the degree (if any) of vertebral involvement and resulting resectability; (2) to image the proximity of the tumor to the spinal cord, which is crucial for radiation planning. SSTs can cause thecal sac or spinal cord compression by extending into the spinal canal through neural foramina, without apparent spine invasion, hence the need for the MRI, which provides a superior image quality than a chest CT scan. The overall treatment strategy depends on the nodal status (“N” stage). For those patients without nodal involvement (“N0”) or with involvement only of the ipsilateral hilar lymph nodes (“N1”), a common approach is to use concurrent induction chemo-radiotherapy, followed by the surgical resection. If obvious mediastinal nodal involvement is seen (“N2 or N3”), the recommendation is for definitive concurrent chemo-radiotherapy without subsequent surgery. Therefore, invasive staging of the mediastinum, either with mediastinoscopy or with EBUS, is mandatory, since it may result in avoiding surgery as part of management. General thoracic radiation therapy (RT) principles apply to the SSTs, such as: (1) use of the CT simulation for tumor and normal tissue imaging; (2) use of 6-10 MV photon energies (unless protons are applied); (3) careful definition of the GTV, Gross Tumor Volume, to include the visible tumor on lung windows and the abnormal lymph nodes on soft tissue windows; (4) adequate margins for the CTV, Clinical Target Volume, and the PTV, Planning Target Volume. In particular, a tendency to have very tight margins around the tumor which is in close proximity to the spinal cord should be avoided at all cost, since this may result in a marginal tumor failure. In comparison to lung cancers in other locations, local tumor progression of a SST can have devastating clinical consequences, resulting in unmanageable pain, limb paralysis and a low quality of life. The commonly used total RT doses are: 45-60 Gy in trimodality therapy (chemo-RT, then surgery) or 60-70 Gy in bimodality therapy (chemo-RT) in 2 Gy daily fractions. The dose-limiting normal structures are usually the spinal cord and brachial plexus. The maximum allowed dose to the spinal cord may need to be higher (54-55 Gy) in SSTs than in other lung cancers (50 Gy) in order not to compromise the minimum dose prescribed to the PTV by attempting to “spare” spinal cord. In patients presenting with severe pain, a simple field arrangement (such as anterior and posterior opposed fields) treating the tumor with wide margins is a good initial option allowing for a quick start, followed by a more advanced planning technique, such as 3-dimensional RT, intensity modulated RT (IMRT) or VMAT. The tolerance of brachial plexus was classically described as a maximum dose of 65 Gy, with recent publications suggesting that higher doses, up to 78 Gy result in 12% risk of Grade>3 radiation-related brachial plexopathy, and that brachial plexopathy is more common as a result of tumor progression than radiation damage. The most quoted prospective clinical trial reporting on treatment outcomes of SSTs is a landmark Phase II SWOG 9416 study, in which 95/110 enrolled patients without disease progression (86%) received thoracic RT to 45 Gy in 1.8 Gy fractions with concurrent cisplatin and etoposide chemotherapy, followed by surgery and further adjuvant chemotherapy. Eligible patients were those with T3-T4 primary tumors and N0 or N1 nodal status. The resection rate was 80% and 75% achieved a complete (R0) resection. The pathologic response rate (no tumor in the specimen or microscopic residual) was 56%; the overall 5 yr survival rate was 44% for all patients and 54% for those with a complete tumor resection. Since then, recognition in the surgical community that operating after RT doses higher than 45 Gy is safe, led to a more common use of the full RT dose, i.e. 60 Gy. If the patient initially planned for trimodality therapy is no longer a surgical candidate or refuses surgery, thoracic RT should continue to definitive dose without interruption. Therefore, it is crucial to perform re-imaging for response assessment in the last week of chemo-RT (if doses of <60 Gy are used) rather than schedule those several weeks later. References: Rusch, V.W., Giroux, D.J., Kraut et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus (initial results of Southwest Oncology Group trial 9416 (Intergroup trial 0160)) . J Thorac Cardiovasc Surg 121: 472–483, 2001. Kwong KF, Edelman MJ, Suntharalingam M et al. High-dose radiotherapy in trimodality treatment of Pancoast tumors results in high pathologic complete response rates and excellent long-term survival. J Thoracic Cardiovasc Surg, 129:1250-57, 2005. Eblan MJ, Corradetti MN, Lukens JN et al. Brachial plexopathy in apical non-small cell lung cancer treated with definitive radiation: dosimetric analysis and clinical implications. Int J Radiat Oncol Biol Phys.85:175-81, 2013.
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SC16.04 - Individualized Extended Lung Cancer Surgery: The Chinese Experience (ID 7011)
15:30 - 15:45 | Author(s): Q. Zhou
- Abstract
Abstract:
Backgroud: Lung cancer is the leading cause of cancer deaths in the world. For patients with advanced non-small cell lung cancer (NSCLC), survival prognosis is very poor with chemotherapy and radiotherapy. However, the possibility of occult metastases may lead to discrepancy between clinical and pathologic staging and underestimation of the disease severity, and how to individualized choose the appropriate patients with locally advanced non-small cell lung cancer for surgery is controversies. In this study, we presented here the Chinese experience: individual precision surgery for locally advanced non-small cell lung cancer based on molecular staging.Methods: We developed several molecular biomarkers and molecular models from Circulation Tumor Cell (CTC ) detection, mi-RNA chip, Gene Chip from 1990. We used these Molecular biomarkers and molecular models for molecular staging, molecular typing, choosing indication of operation and neoadjuvant chemotherapy, predicting postoperative recurrence and prognosis of locally advanced non-small cell lung cancer.Results: We developed two molecular staging model for individualized surgical treatment for locally advanced non-small cell lung cancer involving heart, great vessels or both. 3308 patients with locally advanced non-small cell lung cancer were underwent completely resection of the cancer in the three medical center. The 1-, 3-, 5- and 10 year survival rate were 74.5%,62.3%,31.5% and 22.9%, respectively. We used our molecular staging model for neoadjuvant chemotherapy for 665 patients with locally advanced lung cancer. The 1-, 3-, 5- and 10-year survival rate were 79.35%, 51.46%, 27.39% and 20.34% of the patients, respectively. We used our molecular model to divide N2 lung cancer into invasive N2 and Non-invasive N2 group. We used our molecular models adenocarcinoma and squamous carcinoma to divide T4 lung cancer into high recurrence and low recurrence groups, and help postoperative adjuvant therapy.Conclusion: Our molecular staging and typing models can help us carry out individual precision surgery, predicting prognosis and cancer recurrence of the cancer for locally advancer no-small cell lung cancer.
Information from this presentation has been removed upon request of the author.
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SH03 - WCLC 2016 Scientific Highlights - Surgery and Early Stage NSCLC I - III (ID 485)
- Event: WCLC 2016
- Type: Scientific Highlights
- Track: Early Stage NSCLC
- Presentations: 3
- Moderators:W. Klepetko, M. Krasnik
- Coordinates: 12/06/2016, 07:30 - 08:30, Hall C1
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SH03.01 - Surgery (ID 7123)
07:30 - 07:50 | Author(s): S. Cicenas
- Abstract
- Presentation
Abstract not provided
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SH03.02 - NSCLC Stage I-II (ID 7124)
07:50 - 08:10 | Author(s): E. Fadel
- Abstract
- Presentation
Abstract not provided
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SH03.03 - NSCLC Stage III (ID 7125)
08:10 - 08:30 | Author(s): V. Westeel
- Abstract
- Presentation
Abstract not provided
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Author of
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ED10 - Locally Advanced NSCLC: State-of-the-Art Treatment (ID 279)
- Event: WCLC 2016
- Type: Education Session
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:W. Eberhardt, K. Suzuki
- Coordinates: 12/06/2016, 16:00 - 17:30, Hall C1
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ED10.02 - The Role of Surgery in Stage III NSCLC (ID 6482)
16:25 - 16:45 | Author(s): W. Klepetko
- Abstract
- Presentation
Abstract:
Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease characterized by either locally advanced tumor infiltration and/or mediastinal lymph node involvement. Due to improvements in chemo (CT)- and combined chemoradiation (CRT) therapy protocols, patients with locally advanced stage III NSCLC become potential candidates for curative resection more frequently. According to the TNM-7 classification, stage III NSCLC can be defined by the following T and N subsets: stage IIIA: T3 N1-2, T4 N0-1, T1-2 N2; stage IIIB: T4 N2, T1-4 N3. Five-year survival of stage III is generally around 25% taken all different therapy strategies together. Several studies have shown that induction treatment before surgery is beneficial in resectable cases and selected patients undergoing radical resection may have encouraging 5-year survival rates up to 60%. However, to date, no worldwide consent exists on the general role of surgery in curative attempt. Furthermore, it is still unclear if resectable patients might have greater benefit from induction CT compared to combined induction CRT and if concomitant CRT should be preferred over a sequential treatment. Only a small number of prospective phase II/III trials are available addressing these issues. A phase III trial comparing induction CRT plus surgery (S) with definitive CRT in patients with stage IIIA/N2 published in 2009 has questioned the role of surgery since there was no difference in overall survival (OS) between the two groups [1]. However, the 30-day mortality was unacceptably high (26%) in the subgroup of patients undergoing pneumonectomy and thus patients with CRT and lobectomy had significantly improved OS compared to those with CRT alone. Moreover, several other retrospective series have reported encouraging long-term survival in selected patients undergoing induction treatment followed by radical surgery. The benefit of adding sequential RT to CT prior to surgery (S) in stage IIIA/N2 has been investigated in a recent phase III trial [2]. Patients undergoing CRT/S had a non-significant superior median OS of 37 months compared to 26 months with CT/S. Both groups had similar disease free survival (DFS) and it was concluded that RT did not add any benefit to induction CT prior to surgery. However, those with CRT/S had an objective response, pathological complete response, a R0 resection rate and a mediastinal downstaging more frequently and less local progression compared to CT/S. The question whether to apply RT concomitantly or sequentially to CT has been investigated in a recent meta-analysis [3]. Pooled data from six prospective trials suggested that concomitant CRT, as compared with sequential CRT, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control. However, these patients were treated without surgery and caution should be taken when transferring these conclusions to the neoadjuvant setting before surgery. From the surgical point of view, patients with local tumor invasion (T3-4 N0-1 including Pancoast tumors) have to be treated by different oncological principles than those with mediastinal lymph node (LN) involvement (N2). In patients with T3 tumors invading the chest wall, diaphragm, mediastinal pleura, phrenic nerve or parietal pericardium and N1 involvement, primary resection can be undertaken. Induction therapy may improve local control rates in larger tumors but it remains unclear if systemic treatment is beneficial prior to or after local resection. Intraoperative frozen section of resection margins should be mandatory and reconstruction of resected structures with synthetic material may be necessary. T4 tumors with invasion to the mediastinal structures or vertebral bodies are a unique subset of locally advanced NSCLC and multidisciplinary treatment can be challenging. Well selected patients may benefit from multimodality therapy including surgery and should be treated in well experienced centers [4, 5]. In patients with suspected N2 disease, invasive staging for histological confirmation has been widely accepted as a standard procedure [6]. In case of multilevel and/or bulky N2 disease, surgery should be avoided due to the expected poor outcome. However, it has been well shown that patients in good performance status with single or two level N2 disease with good response after induction therapy may have improved OS when undergoing curative resection [7, 8]. On the other hand, patients with persistent N2 disease after induction treatment tend to have worse OS and high recurrence rates and thus should not undergo surgery. This finding strengthens the impact of invasive re-staging after induction treatment as proposed by recent staging guidelines. In conclusion, selected patients with stage III NSCLC may have beneficial outcome after surgery combined with CT or CRT. However, this holds truth only for cases with response to induction treatment, nodal downstaging and when R0 resection is deemed achievable. Surgery should be avoided in patients with multilevel/bulky N2 disease or persistent mediastinal LN after induction treatment due to the expected poor outcome. The optimal sequence and modality of induction treatment has yet to be defined in larger prospective trails. References [1] Albain KS, Swann RS, Rusch VW, Turrisi AT, Shepherd FA, Smith C, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374:379-86. [2] Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386:1049-56. [3] Aupérin A, Le Péchoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:2181-90. [4] Collaud S, Fadel E, Schirren J, Yokomise H, Bolukbas S, Dartevelle P, et al. En Bloc Resection of Pulmonary Sulcus Non-small Cell Lung Cancer Invading the Spine: A Systematic Literature Review and Pooled Data Analysis. Ann Surg. 2015;262:184-8. [5] Rusch VW. Management of Pancoast tumours. Lancet Oncol. 2006;7:997-1005. [6] De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. 2014;45:787-98. [7] Friedel G, Budach W, Dippon J, Spengler W, Eschmann SM, Pfannenberg C, et al. Phase II trial of a trimodality regimen for stage III non-small-cell lung cancer using chemotherapy as induction treatment with concurrent hyperfractionated chemoradiation with carboplatin and paclitaxel followed by subsequent resection: a single-center study. J Clin Oncol. 2010;28:942-8. [8] Hancock J, Rosen J, Moreno A, Kim AW, Detterbeck FC, Boffa DJ. Management of clinical stage IIIA primary lung cancers in the National Cancer Database. Ann Thorac Surg. 2014;98:424-32; discussion 32.
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OA02 - Novel Targets and Biomarkers in Malignant Pleural Mesothelioma (ID 369)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:L.E. Raez, M. Jakopovic
- Coordinates: 12/05/2016, 11:00 - 12:30, Stolz 2
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OA02.03 - Circulating Fibroblast Growth Factor 18 is Elevated in Malignant Pleural Mesothelioma Patients - A Multi-Institutional Study (ID 5988)
11:20 - 11:30 | Author(s): W. Klepetko
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a rare but devastating malignancy. Despite the search for new promising treatment approaches, the outcome for most MPM patients remains dismal. Therefore, the identification of novel biomarkers is urgently needed in order to identify patients with a better prognosis and to support personalized therapeutic decisions. In our previously published study, we were able to show that fibroblast growth factor 18 (FGF18) is overexpressed in MPM tissue specimens and cell models. The objective of this study was the evaluation of FGF18 as a circulating biomarker in MPM.
Methods:
Plasma was collected from 107 MPM patients at the time of diagnosis or before surgical resection. Samples were included from the Medical University of Vienna, University Hospital Center in Zagreb and from The Concord Repatriation General Hospital and Strathfield Private Hospital in Sydney. Samples from 49 healthy volunteers and from 8 patients with non-malignant pleural diseases served as controls. Circulating FGF18 was measured by enzyme-linked immunosorbent assay and correlated to clinical, pathologic and radiologic parameters.
Results:
Plasma FGF18 level was significantly elevated in MPM patients vs. healthy controls (P<0.0001). A slight increase of circulating FGF18 level was also detected in patients with pleuritis or fibrosis (vs. control, P=0.0067). Sarcomatoid (n=7) morphology was associated with high FGF18 levels when compared to the epithelioid (n=77) histology (P=0.0064). Importantly, MPM patients presenting with FGF18 levels below the median had a significantly longer overall survival when compared to those with high FGF18 levels (median survival 625 versus 382 d, P=0.0038). Data on multivariate analysis, disease-free survival, correlation with other biomarkers and tumor volume will be presented at the conference.
Conclusion:
Our findings reveal that FGF18 is a promising blood-derived candidate biomarker in MPM. Furthermore FGF18 may support the histological classification of MPM and the identification of MPM patients with poor prognosis. .
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OA07 - Lymph Node Metastases and Other Prognostic Factors for Local Spread (ID 376)
- Event: WCLC 2016
- Type: Oral Session
- Track: Surgery
- Presentations: 1
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OA07.01 - Incidence, Local Distribution and Impact of pN2 Skip Metastasis in Patients Undergoing Curative Resection for NSCLC (ID 4177)
14:20 - 14:30 | Author(s): W. Klepetko
- Abstract
- Presentation
Background:
Background: The presence of N2 lymph node (LN) involvement has strong impact on therapy and prognosis in non-small cell lung cancer (NSCLC). N2 LN metastasis may occur by skipping N1 LN stations (N2skip-met). We aim to analyze incidence, local distribution and impact of N2skip-mets in a large cohort of patients undergoing curative resection for NSCLC.
Methods:
Methods: A retrospective non-interventional singe-center cohort study was conducted, assessing all patients undergoing curative resection for NSCLC between 2006 and 2013 at our institution by reviewing medical charts. Incidence of N2skip-mets among these patients was the primary endpoint. Subsequent secondary correlation of clinical parameters was performed using uni- and multivariate logistic and cox regression models.
Results:
Results: In total, 1110 patients were enrolled, with the following pathological LN status: 789 (71%) pN0, 211 (19%) pN1, 105 (9.5%) pN2, 5 (0.5%) pN3. Histological subtype was: adenocarcinoma, n=675 (61%); squamous cell carcinoma, n=309 (28%); other, n=126 (11%). Incidence of N2skip was 55% (47/105). N2skip-mets occurred more frequently in right sided tumors (odds ratio (OR) 2.14, p=0.058) and patients with adenocarcinoma (vs. other, OR 1.54, p=0.19). Presence of N2skip-mets did not correlate with tumor size (ROC, area under curve (AUC) 0.44, p=0.32). Strikingly, presence of N2skip-mets was significantly increased in smokers (OR 3.5, 95% CI 1.38-8.83, p=0.006). Moreover, patients with N2skip-mets were more likely to develop subsequent brain mets (OR 4.13, p=0.06). Overall- and recurrence free survival will be presented at the conference.
Conclusion:
Conclusion: N2skip-mets occur in a high number of patients with N2 disease, with distinct differences in clinicopathologic features. Considering the results of this study, subclassification of N2 disease as recently proposed by the IASLC may have clinical impact in patients with resectable NSCLC.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-026 - Activin A is Associated with Poor Prognosis and Promotes Metastatic Growth in Small Cell Lung Cancer (ID 5888)
14:30 - 14:30 | Author(s): W. Klepetko
- Abstract
Background:
Small cell lung cancer (SCLC) is a devastating malignancy characterized by resistance to therapy and poor clinical outcome. Therefore, identification of novel therapeutic strategies and non-invasive biomarkers that facilitate early detection and predict prognosis is urgently needed. Expression of the growth factor activin A (ActA), a member of the TGF beta superfamily, is deregulated in a number of malignancies. However, to date there is no data on the role of ActA in SCLC.
Methods:
In a cohort of SCLC patients (n=79) and in sex- and age-matched controls (n=66), plasma levels of ActA were measured by ELISA. The diagnostic value of plasma ActA was evaluated by ROC curve analysis. The mRNA and protein expression levels of ActA were analyzed in SCLC cell lines by qRT-PCR and by ELISA, respectively, and one of the cell lines with low baseline ActA expression was transfected with ActA and a control vector. The effect of ActA overexpression on the in vivo growth of SCLC cells was investigated in an orthotopic xenograft model.
Results:
Increased plasma ActA levels were found in patients with SCLC (vs. controls) and ActA levels were elevated in a TNM stage-dependent manner. Moreover, high ActA levels were associated with significantly shorter overall survival and multivariate analysis revealed that plasma ActA concentration is an independent negative prognostic factor in this patient cohort. With an area under the curve of 0.81 (95% CI: 0.74-0-0.88), circulating ActA was identified as a useful biomarker for the diagnosis of SCLC. Expression of ActA in SCLC cell lines was detected in vitro. Furthermore, ActA overexpression increased the metastatic capacity of SCLC cells in our xenograft model.
Conclusion:
Our findings suggest that the measurement of circulating ActA can support the diagnosis and staging of SCLC and, moreover, that it can help to predict the clinical outcome. We also conclude that ActA has a role in the aggressive behavior of this tumor type and that its potential therapeutic relevance needs to be further investigated.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-002 - Inducible Changes in Cell Morphology and Gene Expression Reflecting the Histological Subtypes of Mesothelioma (ID 5405)
14:30 - 14:30 | Author(s): W. Klepetko
- Abstract
Background:
Malignant pleural mesothelioma (MPM) represents an aggressive malignancy with dismal prognosis and limited therapeutic options. MPM occurs in three main histological subtypes: epithelioid, sarcomatoid and biphasic, which are characterized by differences in morphological growth pattern, aggressiveness and patient prognosis. However, the mechanisms and causes responsible for the different cell morphologies are poorly understood. Epithelial-mesenchymal transition (EMT) has been implicated in cancer progression and chemoresistance, but its role in MPM is not well understood. Fibroblast growth factor (FGF) signals promote cell growth, survival and aggressiveness in several tumors including mesothelioma. Aim of this study was to characterize growth factor-induced, EMT-like changes with respect to the MPM histological subtypes.
Methods:
Morphological and behavioral changes of treated cell models were analyzed by morphometry, immunoblotting and functional assays. Alterations in gene or microRNA expression were evaluated via qPCR and array hybridization. Pathway enrichment analysis was based on KEGG.
Results:
In several cell lines established from biphasic MPM, treatment with FGF2 and EGF induced morphological changes reminiscent of EMT and aggressive behavior such as scattering, increased migration, proliferation and invasiveness. Inhibition of the fibroblast growth factor receptors (FGFR) or the MAPK axis via small-molecule inhibitors could prevent these changes and, in cell lines with sarcomatoid-like shape, reverse scattering and induce a more epithelioid morphology. Comparable results were obtained using an engineered FGFR1 enabling contactless activation via blue light. Analyses of genes and microRNAs regulated by FGF2 or EGF showed an overlap with previously established EMT markers but also identified several novel potential markers such as MMP1, ESM1, ETV4, PDL1, ITGA6 or BDKRB2. Blocking the FGFR or MAPK pathways resulted in the opposite regulation of these genes. Inhibition of MMP1 via siRNAs or pharmacological inhibitors prevented FGF2-induced scattering and invasiveness. In unsupervised clustering, the gene expression profiles of solvent- or cytokine-treated cells were associated with those of epithelioid and sarcomatoid MPM, respectively. Immunohistochemistry showed an association of MMP1 as well as phospho-ERK with the sarcomatoid part of tissue specimens from biphasic tumors. Pathway enrichment analysis of differentially expressed genes as well as the targets of altered microRNAs after FGF2 treatment showed that the regulated genes are assigned to categories important for cell growth and aggressive behavior.
Conclusion:
Our data characterize FGFR-mediated signals as important players in MPM aggressiveness and the morphological and behavioral plasticity of mesothelioma cells, leading to a better understanding of the link between the MPM histological subtypes and their influence on patient outcome.
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P3.03-046 - Prognostic Fibrinogen/Leucocyte Score at Diagnosis Predicts Survival and Benefit from Multimodality Treatment in MPM (ID 4179)
14:30 - 14:30 | Author(s): W. Klepetko
- Abstract
Background:
The aim of this study was to identify and validate prognostic and predictive biomarkers in a large cohort of patients with malignant pleural mesothelioma (MPM).
Methods:
We performed a retrospective chart review, including all patients with histologically confirmed MPM, treated at two specialized centers between 1994 and 2014. The effect of different clinical and pathological characteristics and laboratory values on outcome was investigated by using uni- and multivariate logistic and cox regression models.
Results:
Two-hundred ninety-one patients were enrolled (222 males and 69 females). Main histological subtype was epitheloid (n=199, 68%). Multimodality treatment, defined as macroscopic complete resection combined with chemotherapy and/or radiation therapy and/or intracavitary treatment, was performed in 134 (46%) patients. Median overall survival (OS) was 17.7 months from diagnosis. In the multivariate cox regression model, leucocyte count at diagnosis (continuous, hazard ratio (HR) 1.087, p=0.04), fibrinogen at diagnosis (continuous, HR 1.002, p=0.002), histological subtype (epitheloid vs. non-epitheloid, HR 0.064, p=0.006) and age (continuous, HR 1.035, p=0.001) remained as independently significant co-factors influencing OS. ROC curve analyses for predicting 1-year survival revealed an area under the curve (AUC) of 0.72 (p=0.001) for fibrinogen and 0.65 (p=0.001) for leucocytes. Dichotomizing fibrinogen and leucocytes at the median values (550 mg/dl and 8 G/l) revealed a sensitivity of 0.65 and 0.55 and a specificity of 0.69 and 0.61 for predicting 1-year survival, respectively. Combining dichotomized fibrinogen/leucocytes to an inflammation based prognostic score (none, one or both elevated) significantly influenced 1-year survival (p<0.001) and OS (score 0 vs. I, p=0.005; I vs. II, p=0.03). When introducing to the multivariate cox regression model, the fibrinogen/leucocytes score remained as independently prognostic for OS (I vs. O, HR 1.48, p=0.02; II vs. 0, HR 2.26, p<0.001). Strikingly, a significant predictive interaction between the fibrinogen/leucocytes score and treatment modality was observed (p<0.001).
Conclusion:
The inflammation based fibrinogen/leucocytes score predicts OS independently from sex, age, stage, subtype and treatment modality. Multimodality treatment including surgery increases survival selectively in patients with low fibrinogen/leucocytes score.
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P3.04 - Poster Session with Presenters Present (ID 474)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.04-003 - Incidence and Outcome of Female Patients with Previous Breast Cancer Undergoing Curative Resection for Lung Cancer (ID 4178)
14:30 - 14:30 | Author(s): W. Klepetko
- Abstract
Background:
Due to recent improvements in breast cancer (BC) therapy and outcome, female patients with BC may be at higher risk of developing secondary malignancies such as lung cancer (LC). The aim of this study is to evaluate the incidence and outcome of previous BC in female patients with resectable lung cancer.
Methods:
A retrospective non-interventional singe-center cohort study was conducted, assessing all female patients undergoing curative resection for LC between 2006 and 2013 at our institution by reviewing medical charts. Follow-up will be completed in September 2016. Incidence of previous BC among these patients was the primary endpoint. Subsequent secondary correlation of clinical parameters was performed using uni- and multivariate logistic and cox regression models.
Results:
Allover, 463 female patients with LC were identified. The incidence of previous BC was 8.6% (40/463). Mean age was 64.1 years (SD ± 11.5) and was not different between patients with LC and LC/BC. Main histological LC subtype was adeno-carcinoma (64%; squamous cell, 23%; other, 13%). Stage (TNM-7) distribution was: I, 64.5%; II, 22%; III, 12.5%. Lobectomy was the preferred anatomical resection and mean hospital stay was 8.3 days. Complication rate was 7.6%. Recurrence free and overall survival will be presented at the conference. There were no statistical differences between patients with LC/BC and LC with regard to main clinical parameters and short term outcome.
Conclusion:
Due to improvements in breast cancer therapy, a reasonably number of patients developing subsequent lung cancer is observed. Short-term outcome of patients with LC/BC is similar to those with LC.
