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IntroductionBy regulating cell functions such as growth, survival, motility/migration, and invasion, the c-mesenchymal-epithelial transition (c-MET) receptor tyrosine kinase/hepatocyte growth factor (HGF) axis accounts for a critical pathway in malignant pleural mesothelioma.MethodsOverall survival correlations of c-MET and phospho-c-MET immunostainings were investigated in 157 malignant pleural mesothelioma patients for whom paraffin-embedded specimens were referred to our center for pathological diagnosis certification (MESOPATH French National group). Subcellular localization of the activated c-MET receptor after HGF stimulation was assessed in nontumorogenic cell lines.ResultsPositive c-MET expression was found in 119 samples (75.8%), more frequently in the epithelioid subtype (p < 0.0001). Among those 119 positive c-MET specimens, 77 (64.7%) were also positive for phospho-c-MET. Both c-MET and phospho-c-MET scoring were independent of patient gender or age. Phospho-c-MET scoring or localization did not associate with survival. Conversely, patients with a c-MET immunohistochemical staining intensity higher than 1, but exclusively confined to plasma membrane, had a median overall survival of 25 months versus 13 months for all other patients. Only exclusive plasma membrane staining remained significantly associated with a worse prognosis in multivariate analysis (hazard ratio = 2.9, 95% confidence interval 1.0–8.2, p = 0.043). Using the HBEC3 immortalized epithelial cell lines treated with HGF, we showed the physiological relevance of phospho-c-MET nuclear translocation.ConclusionsOur results lighten that, disregarding the intracellular c-MET receptor traffic, only c-MET plasma membrane localization could be a relevant prognosis biomarker in malignant pleural mesothelioma. Whether patients with c-MET plasma membrane immunostaining could beneficiate from c-MET-targeted therapies remains to be established in prospective trials.

Introduction Approximately 2% of lung adenocarcinomas have BRAF (v-Raf murine sarcoma viral oncogene homolog B) mutations, including V600E and other types. Vemurafenib, dabrafenib, and sorafenib as BRAF inhibitors are currently tested in clinical trials, but access for patients is limited. The aim of this study was to document the clinical course of patients treated outside of clinical trials. Methods We conducted a retrospective multicenter cohort study in Europe of patients with advanced BRAF-mutant lung cancer treated with known BRAF inhibitors. Data were anonymized and centrally assessed for age, gender, smoking, histology, stage, local molecular diagnostic results, systemic therapies, and survival. Best response was assessed locally by RECIST1.1. Results We documented 35 patients treated in 17 centers with vemurafenib, dabrafenib, or sorafenib. Median age was 63 years (range 42–85); gender was balanced; 14 (40%) were never smokers; all (100%) had adenocarcinoma; 29 (83%) had V600E; 6 (17%) had other mutations; one of them had a concomitant KRAS mutation. Thirty (86%) patients had chemotherapy in the first line. Overall survival with first-line therapy was 25.3 months for V600E and 11.8 months for non-V600E. Thirty-one patients received one BRAF inhibitor, and four received a second inhibitor. Overall response rate with BRAF therapy was 53%, and disease control rate was 85%. Median progression-free survival with BRAF therapy was 5.0 months, and overall survival was 10.8 months. Conclusions These results confirm the activity of targeted therapy in patients with BRAF-mutant lung adenocarcinoma. Further trials are warranted to study combination therapies and drug resistance mechanisms.

Antibodies specific for human p53 were analysed in sera of lung cancer patients. We detected p53 antibodies in the sera of 24% (10/42) of patients with lung carcinoma. The distribution was as follows: 4/9 small-cell lung carcinomas (SCLCs), 2/18 squamous cell lung carcinomas (SCCs), 2/10 adenocarcinomas (ADCs) and 2/5 large-cell lung carcinomas (LCCs). p53 antibodies were always present at the time of diagnosis and did not appear during progression of the disease. Using an original peptide-mapping procedure, we precisely localised the p53 epitopes recognised by p53 antibodies. Immunodominant epitopes reacting with antibodies were localised in the amino and carboxy termini of the protein, similar to those found in breast carcinoma patients or in animals immunised with p53. In light of these data, we suggest that p53 antibodies occur via a self-immunisation process that is the consequence of p53 accumulation in tumour cells. p53 antibodies were also detected in two patients without detected malignant disease. One of these patients died 6 months later of lung carcinoma, suggesting that p53 antibodies may be a precocious marker of p53 alteration. Images Figure 2

Background Concomitant platinum-based chemotherapy and radiotherapy (CT-RT) is the recommended treatment for unresectable locally advanced stage III non-small cell lung cancer (NSCLC). We conducted a phase II study to evaluate the efficacy and safety of fractionated oral vinorelbine with cisplatin as induction CT followed by CT-RT. Methods Patients with stage III NSCLC received 2 induction cycles of intravenous vinorelbine 25 mg/m2 and cisplatin 80 mg/m2 on day 1 and oral vinorelbine 60 mg/m2 on day 8. Responding patients received 2 more cycles of cisplatin 80 mg/m2 on day 1 and oral vinorelbine 20 mg on days 1, 3 and 5 concomitantly with radiotherapy 2 Gy daily, 5 days/week for a total of 66 Gy. Results Seventy patients, median age 61 years, were enrolled. Overall response rate (ORR) was 50.0%; Disease Control Rate was 81.42%. Median PFS was 14.58 months [95% CI, 10.97-18.75]. Median OS was 17.08 months [95% CI, 13.57-29.57]. One-year and 2-year survival rates were 68.6% [95% CI, 57.7-79.4] and 37%. One patient had a grade 3 pulmonary radiation injury and 26.5% had graded 1/2 esophagitis. Conclusion In non-operable IIIA-IIIB NSCLC, the combination oral vinorelbine (fractionated fixed dose) plus cisplatin, during concomitant CT-RT, could offer a well-tolerated option, with comparable activity to I.V. vinorelbine-based chemoradiotherapy regimens. Trial registration ClinicalTrials.gov, NCT01839032

International audience; While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months. To help define the nosological relationships of these tumors, we compared their transcriptomic profiles with those of SMARCA4-mutated small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs), SMARCB1-inactivated malignant rhabdoid tumors (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations). Gene profiling analyses demonstrated that these tumors were distinct from lung carcinomas but related to MRTs and SCCOHTs. Transcriptome analyses, further validated by immunohistochemistry, highlighted strong expression of SOX2, a marker that supports the differential diagnosis of these tumors from SMARCA4-deficient lung carcinomas. The prospective recruitment of cases confirmed this new category of 'SMARCA4-deficient thoracic sarcomas' as readily recognizable in clinical practice, providing opportunities to tailor their therapeutic management.

e16560 Background: The IFCT–GFPC 0502 phase III study reported a prolongation of progression-free survival with maintenance with either gemcitabine or erlotinib versus observation after cisplatin-gemcitabine induction chemotherapy in advanced NSCLC. The aim of this analysis is to assess the incremental cost-effectiveness ratio (ICER) of these strategies in the global population and in pre specified sub-groups. Methods: A cost-utility analysis was performed to evaluate ICER of maintenance therapy with either gemcitabine or erlotinib, compared to observation, from randomization until end of follow up. Direct medical costs (including drugs costs, hospitalization, follow-up examinations, second-line treatment and palliative costs) were prospectively collected per patient alongside the trial, until death, from the third party payer perspective. Utility data were extracted from literature. Sensitivity analyses were performed. Results: The ICER for maintenance therapy with gemcitabine and erlotinib were respectively 84,011 and 183,261 euros per quality-adjusted life years (QALY). Gemcitabine maintenance therapy had a favourable ICER in patients with PS = 0 (51,168 €/Qaly), in responders to induction chemotherapy (65,554€/Qaly) and in patients with squamous cell carcinoma (44,884€/Qaly); erlotinib had a favourable ICER in patients with PS = 0 (162,371 €/Qaly) and objective response to induction (101,569 €/Qaly ). Conclusions: Gemcitabine and erlotinib maintenance therapy have acceptable ICER but with a wide variation function of histology, PS and response to the first line chemotherapy.

7574 Background: Continuous exposure of tumor cells to maintenance therapy in advanced NSCLC might lead to resistance to subsequent treatments. IFCT–GFPC 0502 study showed a progression-free survival (PFS) benefit with gemcitabine (G) or erlotinib (E) maintenance compared to observation (O) after cisplatin-G induction chemotherapy. The trial included a pre-defined second-line therapy with pemetrexed (P), allowing post-hoc assessment of its efficacy according to previous maintenance treatment or treatment-free interval. Methods: Stage IIIB/IV NSCLC patients (pts) with a PS of 0-1 were randomized after 4 cycles of cisplatin-G chemotherapy to O or to receive maintenance therapy with G or E until disease progression. P was given as second-line treatment on disease progression in all arms. PFS and OS were assessed from the beginning of P therapy according to randomization arm. Tumor response to P and tolerance were also analyzed. Results: Of the 464 pts randomized to either O (155), G (154) or E (155), 360 pts (78 %) received P as second-line therapy, i.e. 130 (84%), 114 (74%) and 116 (75%) in O, G and E arm, respectively. Baseline characteristics remained well balanced between arms (overall median age of 58 years, 28% female, 91% stage IV, 41% PS 0, 65/19/16%, adenocarcinoma/squamous/other, 10% non-smokers and 56% responders to induction CT). Median number of delivered P cycles was 3 (1-40) in all arms. Response rate was 19%, 7% and 15% for non-squamous pts in O, G and E, respectively. Median PFS did not significantly differ between G and O (4.2 vs 3.9 months, HR [95% CI] 0.81 [0.62-1.06]) or E and O (4.2 vs 3.9 months, HR 0.83 [0.64-1.09]). OS data showed a non-significant improvement with G vs O (HR 0.81 [0.61-1.07]) or E vs O (HR 0.80 [0.61-1.05]), with a median of 7.5, 8.3 and 9.1 months for O, G and E, respectively. Results were similar when analysis was restricted to non-squamous pts. Grade 3-4 treatment-related AEs were similar in O (33.1%), G (31.6%) and E (25%). Conclusions: Maintenance therapy with continuation of G or switch to E does not impair the efficacy of second-line P by comparison with administration after a treatment-free interval.

Background Fiberoptic bronchoscopy (FOB) is a useful diagnosis tool in low-burden countries for patients with suspected pulmonary tuberculosis (TB) who are smear-negative or sputum-scarce. This study sought to determine the accuracy of the Xpert® MTB/RIF (XP) assay using FOB samples. Methods We retrospectively reviewed clinical, radiological, and microbiological characteristics of 175 TB-suspected patients requiring diagnostic FOB (bronchial aspirate or bronchoalveolar lavage) with XP assay. Polymerase chain reaction (PCR) and smear microscopy (SM) performances were first compared to culture, then to the final diagnosis, established based on clinical or radiological evolution when cultures were negative. Results Of the total 162 included patients, 30 (18.5%) had a final diagnosis of pulmonary TB, with positive cultures reported in 23. As compared to culture, sensitivity and specificity values were 80.0% and 98.6% for the XP assay, and 25.0% and 95.8% for SM, respectively. As compared to final diagnosis, the corresponding performance values were 60.0% and 100.0% for the XP assay, and 16.7% and 95.5% for SM, respectively. The sensitivity of the XP assay was significantly higher than that of SM in both cases (p = 0.003 and p = 0.001). Concerning the final diagnosis, both XP assay and culture sensitivities were similar (60% vs. 66.7%). PCR assay enabled pulmonary TB to be diagnosed earlier in 13 more cases, compared to SM. Conclusion Our study has confirmed the clinical benefits provided by XP assay compared to SM for the early diagnosis of suspected pulmonary TB cases requiring FOB, on per procedure samples, especially in a low TB-burden country.

Malignant pleural mesothelioma (MPM) is a rare, very aggressive, primary tumor with a poor prognosis. During this thesis, we wanted to identify new biomarkers of MPM by testing the influence of the RASSF/Hippo pathway inactivation on the survival of the 448 patients included in the clinical trial MAPS (IFCT- GFPC-0701). We also wanted to understand which functions and signals essential to cellular homeostasis, linked to RASSF/Hippo signaling pathway, are disturbed during the mesothelial cell transformation process. Inactivation of RASSF/Hippo members was studied by methylation-specific PCR (MS-PCR) and their influence on the survival of the 448 patients included in the MAPS clinical trial tested in uni- and multivariate analysis before being validated by bootstrap. We also mimed in cell, by RNA interference, several members of the Hippo pathway inactivation in human mesothelial cells lines (MSTO-211H, H2452, H28 and H2052). We have identified several biomarkers of MPM: i) MST1 kinase whose inactivation is a factor of poor prognosis, ii) amphiregulin whose cytoplasmic expression is on the contrary a factor of good prognosis and finally iii) CD44 whose high expression is a diagnostic tool for MPM. In cell we demonstrate that RASSF/Hippo pathway alterations induce an inappropriate activity of YAP, one Hippo end effector: the poorer prognosis of patients with inactivation of MST1 is thus explained by the fact that, by regulating YAP activity, MST1 controls the apoptosis/proliferation balance and prevents invasion and growth without adhesion from mesothelial cells. In its absence, these cellular processes are deregulated. This work finally demonstrates the importance of the CD44/RASSF1A/MST1 axis in controlling appropriate YAP activity and mesothelial cell homeostasis. The understanding of the cellular disorders induced by the of the RASSF/Hippo pathway deregulation designates YAP as a potential therapeutic target in patients with MPM and presenting alterations of this signaling pathway.; Le mésothéliome pleural malin (MPM) est une tumeur primitive de la plèvre, rare, très agressive, avec un pronostic sombre. Nous avons souhaité au cours de ce travail de thèse, identifier de nouveaux biomarqueurs du MPM en testant l’influence de l’inactivation des membres de la famille RASSF/Hippo sur la survie des 448 patients inclus dans l’essai clinique MAPS (IFCT-GFPC-0701). Nous souhaitions également comprendre quelles fonctions et signalisations essentielles à l’homéostasie cellulaire, auxquelles participe la voie de signalisation RASSF/Hippo, sont perturbées lors du processus de transformation des cellules mésothéliales. L’inactivation des membres de la voie a été étudiée par PCR spécifique de méthylation (MS-PCR) et leur influence sur la survie des 448 patients inclus dans l’essai clinique MAPS testée en analyse uni- et multivariée avant d’être validée par boostrap. D’autre part, nous avons mimé in cell, l’inactivation par ARN interférence de plusieurs membres de la voie Hippo dans des cellules de lignées mésothéliales humaines (MSTO-211H, H2452, H28 et H2052). Nous avons pu identifier plusieurs biomarqueurs du MPM : i) la kinase MST1 dont l’inactivation est un facteur de mauvais pronostic, ii) l’amphiréguline dont l’expression cytoplasmique est au contraire un facteur de bon pronostic et enfin iii) le CD44 dont l’expression élevée constitue un outil diagnostique du MPM. Les approches in cell, nous ont permis de démontrer que les altérations de la voie RASSF/Hippo induisent une activité inappropriée de l’effecteur terminal YAP : le moins bon pronostic des patients présentant une inactivation de MST1 s’explique ainsi par le fait qu’en régulant l’activité de YAP, MST1 contrôle la balance apoptose/prolifération et prévient l’invasion et la croissance sans adhésion. En son absence, ces processus cellulaires sont dérégulés. Ce travail démontre l’importance de l’axe CD44/RASSF1A/MST1 dans le contrôle d’une activité appropriée de YAP et de l’homéostasie des cellules mésothéliales. La compréhension des désordres cellulaires induits par la dérégulation de le voie RASSF/Hippo, désigne YAP comme cible thérapeutique potentielle chez les patients atteints de MPM et présentant des altérations de cette voie de signalisation.