Specific needs in lung cancer patients

Abstracts / Lung Cancer 77 (2012) S1–S20

via overexpression of EGFR. Another study has found a significant association between EGFR mutation status and miR-21 expression [188]. However these data were not confirmed in the larger number of NSCLC samples evaluated by Voortman and colleagues [9–12]. Our results suggest that miR-590-5p and miR-655 are involved in apoptosis. The higher levels of miR-590-5p correlate with Bcl2 positivity and pro-apoptotic protein BAX seems to be regulated by miR-655. Translation of proteins responsible for cell cycle progression, such as p16 and PCNA proteins, may be regulated by miR-491-3p. There is a negative correlation between expression of miR-491-3p and these two proteins. The level of LRP protein responsible for drug resistance in lung cancer patients seems to be regulated by miR-255. Within our cohort of NSCLC patients we did not find any correlations between the expression profiles of the above mentioned miRNAs and survival. In conclusion, it is clearly evident from all these studies using gene profiling that most emerging miRNA signatures are not fully overlapping. These results might be explained by different specimens tumour types, stage, regimens and small sample size. References [1] Boyd MR, Kenneth DP. Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen. Drug Dev Res 2005;34(1):91–109. [2] Gaur A, Jewell DA, Liang Y, et al. Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res 2007;67(6):2456–68. [3] Blower PE, Verducci JS, Lin S, et al. MicroRNA expression profiles for the NCI-60 cancer cell panel. Mol Cancer Ther 2007;6(5):1483–591. [4] Yanaihara N, Caplen N, Bowman E, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 2006;9(3):189–98. [5] Yu SL, Chen HY, Chang GC, et al. MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 2008;13(1):48–57. [6] Markou A, Tsaroucha EG, Kaklamanis L, et al. Prognostic value of mature microRNA-21 and micro-RNA-205 overexpression in nonsmall cell lung cancer by quantitative real-time RT-PCR. Clin Chem 2008;54(10):1696–704. [7] Raponi M, Dossey L, Jatkoe T, et al. MicroRNA classifiers for predicting prognosis of squamous cell lung cancer. Cancer Res 2009;69(14):5776–83. [8] Patnaik SK, Kannisto E, Knudsen S, Yendamuri S. Evaluation of microRNA expression profiles that may predict recurrence of localized stage I non-small cell lung cancer after surgical resection. Cancer Res 2010;70(1):36–45. [9] Voortman J, Goto A, Mendiboure J, et al. MicroRNA expression and clinical outcomes in patients treated with adjuvant chemotherapy after complete resection of non-small cell lung carcinoma. Cancer Res 2010;70(21):8288–98. [10] Landi MT, Zhao Y, Rotunno M, et al. MicroRNA expression differentiates histology and predicts survival of lung cancer. Clin Cancer Res 2010;16(2):430–41. [11] Weiss GJ, Bemis LT, Nakajima E, et al. EGFR regulation by microRNA in lung cancer: correlation with clinical response and survival to gefitinib and EGFR expression in cell lines. Ann Oncol 2008;19(6):1053–9. [12] Seike M, Goto A, Okano T, et al. MiR-21 is an EGFR-regulated antiapoptotic factor in lung cancer in never-smokers. Proc Natl Acad Sci U S A 2009;106(29):12085–90.

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fistula, pleural effusions, ribs, and pleura) [4–8]. Respiratory symptoms can also result from complications chemotherapy and radiotherapy induced lung toxicity (airway stenosis and necrosis, fistula formation, hemoptysis) [9–11]. Comorbid conditions (such as COPD, heart failure, pulmonary embolism, prior lung resection, malnutrition) cause or contribute to respiratory symptoms. Symptoms referable to distant extrathoracic metastase to bone, brain, spinal cord and liver pose additional problems that require a specific response for optima symptom control. A significant number of patients have respiratory symptoms as the result of mechanical (anatomic) effects of lung cancer, such as major airway obstruction, postobstructive pneumonia, fistulae between airways and other intrathoracic organs, pleural effusion, and parakusis of diaphragm and vocal cords. In such patients, pharmacologic (noninvasive) therapies may be inadequate to palliate respiratory symptoms. Several invasive techniques are available to benefit this selected group of patients [12]. Summary of most important recomendations for symptomatic lung cancer patients. For patients who complain of dyspnea, it is recommended that they be evaluated for potentially correctable causes, such as localized obstruction of a major airway, a large pleural effusion, pulmonary emboli, or an exacerbation of coexisting COPD or congestive heart failure. If one of these problems is identified, treatment with appropriate methods is recommended. For patients whose dyspnea does not have a treatable cause, opioids are recommended. Also recommended are other pharmacologic approaches such as oxygen, bronchodilators, and corticosteroids. For patients who have troublesome cough, it is recommended that they be evaluated for treatable causes. For patients who have troublesome cough without a treatable cause, it is recommended that opioids be used to suppress the cough. For patients with large-volume hemoptysis, bronchoscopy is recommended to identify the source of bleeding, followed by endobronchial treatment. In patients with symptomatic malignant pleural effusions, thoracentesis is recommended as the first drainage procedure for symptom relief. In patients that recur after thoracentesis, chest tube drainage and pleurodesis are recommended. In patients with symptomatic SVCS obstruction due to SCLC, chemotherapy is recommended and in patients NSCLC, stent insertion and/or radiation therapy are recommended. Stents are also recommended for symptomatic patients obstruction who fail to respond to chemotherapy or radiation therapy. For patients with a malignant transesophageal fistula and bronchoesophageal fistula, stenting of esophagus, airway, or both should be considered for symptomatic relief are not recommended [12]. Early integration of palliative care for patients with advanced lung cancer is a clinically meaningful and feasible care model that has effects on survival and quality of life that are similar to the effects of first-line chemotherapy in such patients [13–16].

Specific needs in lung cancer patients Jana Skˇriˇcková. Department of Respiratory Diseases and TB, University Hospital and Medical Faculty of Masaryk University, Brno, Czech Republic Lung cancer is the most important cause of death due to cancer in the world. Even with best available treatment, survival 5 years postdiagnosis is approximately 15% [1], and about 80% of patients die within 1 year of diagnosis [2]. The poor prognosis is often caused by a late diagnosis as the presentation usually occurs when the disease is advanced. Patients develop burdensome symptoms arising from disease or treatments, particularly in the advanced stage of illness [3]. Pulmonary symptoms that may require palliation include those caused by the primary cancer itself (dyspnea, wheezing, cough, hemoptysis, chest pain),or locoregional metastases within the thorax (superior vena cava syndrome – SVCS, tracheoesophageal

References [1] Schofield P, Ugalde A, Carey M, Mileshkin L, Duffy M, Ball D, et al. Lung cancer: challenges and solutions for supportive care intervention research. Palliat Support Care 2008;6:281–7. [2] Potter J, Higginson IJ. Pain experienced by lung cancer patients: a review of prevalence, causes and pathophysiology. Lung Cancer 2004;43:247–57. [3] Sebastiano Mercadante S, Vitríno V. Pain in patients with lung cancer: pathophysiology and treatment. Lung Cancer 2010;68:10–5. [4] Brown J, Thorpe H, Napp V, et al. Assessment of quality of life in the supportive care setting of the big lung trial in non-small-cell lung cancer. J Clin Oncol 2005;23:7417–27. [5] Chute CG, Greenberg ER, Baron J, et al. Presenting conditions of 1539 population-based lung cancer patients by cell type and stage in New Hampshire and Vermont. Cancer 1985;56:2107–11. [6] Hamilton W, Peters TJ, Round A, et al. What are the clinical features of lung cancer before the diagnosis is made? A population based case–control study. Thorax 2005;60:1059–65.

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[7] Wurschmidt F, Bunemann H, Heilmann HP. Small cell lung cancer with and without superior vena cava syndrome: a multivariate analysis of prognostic factors in 408 cases. Int J Radiat Oncol Biol Phys 1995;33:77–82. [8] Kvale PA. Chronic cough due to lung tumors: ACCP evidence-based clinical practice guidelines. Chest 2006;129:147S–53S; Bennett R, Maskell N. Management of malignant pleural effusions. Curr Opin Pulm Med 2005;11:296–300. [9] Suzuki M, Otsuji M, Baba M, et al. Bronchopleural fistula after lung cancer surgery: multivariate analysis of risk factors. J Cardiovasc Surg (Torino) 2002;43:263–7. [10] Kong FM, Ten Haken R, Eisbruch A, et al. Non-small cell lung cancer therapyrelated pulmonary toxicity: an update on radiation pneumonitis and fibrosis. Semin Oncol 2005;32:S42–54. [11] Miller KL, Shafman TD, Anscher MS, et al. Bronchial stenosis: an underreported complication of high-dose external beam radiotherapy for lung cancer? Int J Radiat Oncol Biol Phys 2005;61:64–9. [12] Paul A, Kvale PA, Selecky PA, Udaya BS, Prakash UBS. Palliative care in lung cancer. ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition). Chest 2007;132:368S–403S. [13] Brown J, Thorpe H, Napp V, et al. Assessment of quality of life in the supportive care setting of the Big Lung Trial in non-small-cell lung cancer. J Clin Oncol 2005;23:7417–27. [14] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis usány updated data on individual patients from 52 randomised clinical trials. BMJ 1995;311:899–909. [15] Spiro SG, Rudd RM, Souhami RL, et al. Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life. Thorax 2004;59:828–36. [16] Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010;363:733–42.

http://dx.doi.org/10.1016/j.lungcan.2012.05.026 MicroRNAs as a new class of lung cancer biomarkers Ondrej Slaby. Masaryk Memorial Cancer Institute, Brno, Czech Republic MicroRNAs (miRNAs) are a class of naturally occurring, short noncoding, single stranded RNAs, that regulate gene expression at the post-transcriptional level, by binding through partial sequence homology to the untranslated region (3 UTR) of mammalian target mRNAs and causing translational inhibition and/or mRNA degradation. Aberrant expression of miRNAs occurs in many types of cancers, some of which function as tumor suppressor genes or oncogenes [1]. More than 350 papers has been indexed in the PubMed database focusing miRNAs significance in lung cancer, only a few of the recent remarkable studies is mentioned bellow. Changes in the expression profiles of miRNAs have been observed in the lung cancer tissue enabling not only to discriminate normal lung from tumorous tissues, but also more accurate stratification of histological subtypes, even in small biopsies/aspirates of poorly differentiated tumors [2]. Example of independently validated biomarker for histological subclassification of non-small cell lung cancer (NSLCC) is miR-205 with a high specificity for squamous cell lung carcinoma reaching sensitivity of 96% and specificity of 90% [2]. Functional studies indicate that selected miRNAs with altered expression levels in tumor tissue act as tumor suppressors and oncogenes in lung cancer pathogenesis. These findings significantly extend concept of molecular pathogenesis of lung cancer and have shown great potential for miRNA as a novel class of therapeutic targets [1]. Several investigations have also described the ability of miRNA expression profiles to predict prognosis in NSCLC patients [3,4]. For example, well known oncogenic miR-21 is significantly associated with disease progression and survival in stage I lung cancer which was observed in more than 300 NSCLC patients that originated from three independent cohorts [3]. Further, 34-miRNA prognostic signature was identified and validated by Solexa sequencing in 527 stage I NSCLC patients enabling accurate prediction of relapse-free survival [4]. miRNA occurrence has been repeatedly observed also in serum and plasma, and circulating miRNAs as novel minimally invasive biomarkers have

indicated reasonable sensitivity for cancer detection. The levels of four serum miRNAs (miR-486, miR-30d, miR-1 and miR-499) were significantly associated with overall survival in stage I–IIIa NSCLC patients [5]. Specific miRNA signature was identified also in plasma samples collected 1–2 y before onset of the disease that predict cancer development and prognosis, and could be potentially useful in the selection of high-risk individuals who need to undergo spiral-CT surveillance [6]. More recently, lung cancer specific miRNA signatures were identified in sputum enabling early non-invasive diagnosis and histological classification of NSCLC with significantly improved sensitivity and specificity compared to conventional cytological examination [7]. This lecture covers introduction to miRNA biology, miRNA involvement in the hallmarks of cancer, and the state of the art and perspectives in the discovery and clinical implementation of miRNAs as a new class of biomarkers in the lung cancer.

References [1] Slaby O, editor. MicroRNAs in solid cancer: from biomarkers to therapeutic targets. Nova Science Publishers; 2012., ISBN 978-1-61324-514-9, 194 pp. [2] Lebanony D, Benjamin H, Gilad S, Ezagouri M, Dov A, Ashkenazi K, et al. Diagnostic assay based on hsa-miR-205 expression distinguishes squamous from nonsquamous non-small-cell lung carcinoma. J Clin Oncol 2009;27:2030–7. [3] Saito M, Schetter AJ, Mollerup S, Kohno T, Skaug V, Bowman ED, et al. The association of microRNA expression with prognosis and progression in early stage, non-small cell lung adenocarcinoma: a retrospective analysis of three cohorts. Clin Cancer Res 2011;17:1875–7. [4] Lu Y, Govindan R, Wang L, Liu PY, Goodgame B, Wen W. MicroRNA profiling and prediction of recurrence/relapse-free survival in stage I lung cancer. Carcinogenesis 2012, http://dx.doi.org/10.1093/carcin/bgs100. [5] Hu Z, Chen X, Zhao Y, Tian T, Jin G, Shu Y, et al. Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small cell lung cancer. J Clin Oncol 2010;28:1721–6. [6] Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, et al. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A 2011;108(9):3713–8. [7] Xing L, Todd NW, Yu L, Fang H, Jiang F. Early detection of squamous cell lung cancer in sputum by a panel of microRNA markers. Mod Pathol 2010;23:1157–67.

http://dx.doi.org/10.1016/j.lungcan.2012.05.027 ETOP activity in the field of biomarkers and predictors R.A. Stahel 1,∗ , S. Peters 2 , F. Blackhall 3 , L. Bubendorf 4 , O. Dafni 5 , K. Kerr 6 , M. Taron 7 , E. Thunnissen 8 , W. Weder 9 , E. Smit 10 , R. Rosell 7 . 1 Clinic of Oncology, University Hospital, Zurich, Switzerland, 2 Multidisciplinary Oncology Center, Lausanne, Switzerland, 3 The Christie NHS Foundation Trust, Manchester, United Kingdom, 4 University Hospital Basel, Institute for Pathology, Basel, Switzerland, 5 Frontiers of Science, Athens, Greece, 6 Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, United Kingdom, 7 ICO-Hospital Germans TriasiPujol, Barcelona, Spain, 8 Department of Pathology, VUMC Amsterdam, Amsterdam, Netherlands, 9 Thoracic Surgery, University Hospital Zurich, Switzerland, 10 University Medical Center Amsterdam, Netherlands Lungscape is a translational research project designed by ETOP. It aims to address the challenges of studying the molecular epidemiology of lung cancer by coordinating and harmonizing the procedures of a group of lung cancer specialists working in translational research across Europe and allowing analysis of larger series of cases. This initiative has the potential to expedite knowledge of the prevalence and context of current and emerging molecular biomarkers with clinical significance and facilitate more rapid translation of biomarker knowledge to the clinic. Lungscape is evolving in step-wise fashion, starting with a retrospective analysis of up to 2400 completely resected NSCLC from16 institutions. The fundamental approach of Lungscape was to build a decentralized biobank (termed iBiobank) of samples from lung cancer patients with annotated clinical and pathological data and