Outcome In Malignant Pleural Mesothelioma Research Articles

CHST4 Gene as a Potential Predictor of Clinical Outcome in Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) develops primarily from asbestos exposures and has a poor prognosis. In this study, The Cancer Genome Atlas was used to perform a comprehensive survival analysis, which identified the CHST4 gene as a potential predictor of favorable overall survival for patients with MPM. An enrichment analysis of favorable prognostic genes, including CHST4, showed immune-related ontological terms, whereas an analysis of unfavorable prognostic genes indicated cell-cycle-related terms. CHST4 mRNA expression in MPM was significantly correlated with Bindea immune-gene signatures. To validate the relationship between CHST4 expression and prognosis, we performed an immunohistochemical analysis of CHST4 protein expression in 23 surgical specimens from surgically treated patients with MPM who achieved macroscopic complete resection. The score calculated from the proportion and intensity staining was used to compare the intensity of CHST4 gene expression, which showed that CHST4 expression was stronger in patients with a better postoperative prognosis. The median overall postoperative survival was 107.8 months in the high-expression-score group and 38.0 months in the low-score group (p = 0.044, log-rank test). Survival after recurrence was also significantly improved by CHST4 expression. These results suggest that CHST4 is useful as a prognostic biomarker in MPM.

High-intensity statins are associated with improved clinical activity of PD-1 inhibitors in malignant pleural mesothelioma and advanced non-small cell lung cancer patients.

In preclinical models, statins showed vaccine adjuvant activities and synergized with PD-1 inhibitors. We analyzed the impact of statin treatment on clinical outcome in thoracic cancer patients treated with PD-1 inhibitors. A total of 82 malignant pleural mesothelioma (MPM) and 179 advanced non-small cell lung cancer (aNSCLC) patients treated with PD-1 inhibitors as second or further line treatment were examined. Seventy-seven MPM patients treated with standard chemotherapy were analyzed as control cohort. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were calculated. Among 253 patients with available data, statin use was associated with increased ORR (32% versus 18%, P=.02), PFS (median 6.7 versus 2.9 months, hazard ratio [HR] 0.57, 95% CI 0.39-0.83, P<.01), and OS (median 13.1 versus 8.7 months, HR 0.67, 95% CI 0.45-1.00, P=.05). In the control MPM cohort treated with chemotherapy (n=77), no association was found. MPM patients who used statins showed improved ORR (22% versus 6%, P=.05), PFS (median 6.7 versus 2.4 months, P<.01), and OS (median not reached versus 6.0 months, P=.01). In aNSCLC patients, statin use was associated with improved ORR (40% versus 22%, P=.04) and PFS (median 7.8 versus 3.6 months, P=.03), but no significant difference in OS was found (median 13.1 versus 10.1 months, P=.30). Multivariable analysis confirmed the correlation between statin use and better PFS and OS in MPM and better PFS in aNSCLC. In the whole cohort, high but not low/moderate-intensity statins were associated with better OS compared to no user (P=.02 and P=.59, respectively). Our study showed that statins are associated with better clinical outcome in MPM and aNSCLC patients treated with PD-1 inhibitors in an intensity-dependent manner.

1902P Association of high-intensity statins with clinical outcome in malignant pleural mesothelioma and advanced non-small cell lung cancer patients treated with PD1 inhibitors

1902P Association of high-intensity statins with clinical outcome in malignant pleural mesothelioma and advanced non-small cell lung cancer patients treated with PD1 inhibitors

MS25.01 Impact of Tumor Volume on Outcome: What Are the Limitations?

MS25.01 Impact of Tumor Volume on Outcome: What Are the Limitations?

P2.06-21 Low Intratumoral Platinum Concentration is Associated with Unfavorable Clinical Outcome in Malignant Pleural Mesothelioma

P2.06-21 Low Intratumoral Platinum Concentration is Associated with Unfavorable Clinical Outcome in Malignant Pleural Mesothelioma

Prognostic factors and treatment outcomes of malignant pleural mesothelioma in Eastern Asian patients - A Taiwanese study.

There are scarce reports on the prognostic factors and treatment outcomes of patients with malignant pleural mesothelioma (MPM) in Asia. This study aimed to address these matters in a real-world setting. Medical records of patients with histologically proven MPM diagnosed between 1977 and 2016 at the National Taiwan University Hospital were reviewed. Variables including age, gender, performance status, asbestos exposure, smoking history, histology subtype, staging, and treatment received were recorded. All patients were followed until death or March 1st, 2017. Survival and prognostic factors were analyzed by the Kaplan-Meir method and the Cox proportional hazard model. A total of 93 patients was identified, including 65 men and 28 women. An increasing trend of MPM cases diagnosed was observed in the past 40 years. Stage I/II disease (HR 0.24, 95% CI 0.13-0.46) and epithelioid histology (HR 0.42, 95% CI 0.23-0.75) were associated with favorable prognosis, whereas age ≥70 years (HR 2.66, 95% CI 1.36-5.22) and ECOG ≥2 (HR 5.03, 95% CI 2.69-9.4) were poor prognostic factors. After adjustment for prognostic factors, surgery in stage I-III MPM (HR 0.36, 95% CI 0.15-0.83) and systemic therapy in stage III/IV disease (HR 0.42, 95% CI 0.19-0.94) conferred a survival benefit. This is one of the largest case series of MPM reported in Asia outside of Japan. Prognostic factors in the study population included age, performance status, stage, and histology subtype. Surgery in potentially resectable disease and systemic therapy in advanced MPM confer a survival benefit in Asian patients.

219P Outcomes of malignant pleural mesothelioma (MPM) patients (p) treated after first line chemotherapy (CT)

219P Outcomes of malignant pleural mesothelioma (MPM) patients (p) treated after first line chemotherapy (CT)

Prognostic and Clinicopathological Significance of BAP1 Protein Expression in Different Types of Cancer-A Meta-Analysis.

The prognostic value of BRCA1-associated protein 1 (BAP1) expression in different cancer types remains controversial. The aim of this study was to identify the prognostic and clinicopathological significance of BAP1 gene expression. The PubMed, Web of Science, and Embase databases were searched comprehensively for relevant studies. The pooled effects were calculated to investigate the association of BAP1 expression with cancer prognosis and clinicopathological features. The χ2 and I2 tests were performed to evaluate heterogeneity among the enrolled articles. If the p > 0.05 and I2 < 50%, a fixed-effects model was applied; and if the p < 0.05 and I2 > 50%, we used a random-effects model. A total of 26 studies covering 8043 patients were included in the meta-analysis. The correlation between BAP1 expression and patient survival was evaluated for 10 different cancer types. The pooled hazard ratio (HR) of BAP1 expression and overall survival (OS) was 0.83 (95% confidence interval [CI]: 0.61-1.12) with heterogeneity (I2 = 85.8%, p < 0.001), which indicated that the expression of BAP1 had no obvious impact on patient survival in the all-cancer cohort. However, subgroup analyses indicated that cancer type, rather than other parameters (geographic region, detection method, sample size, or comparison method), lead to this heterogeneity. BAP1 expression was a favorable predicative factor for OS in clear cell renal cell carcinoma (HR = 0.57, 95% CI: 0.47-0.69), non-small cell lung cancer (HR = 0.55, 95% CI: 0.32-0.96), and uveal melanoma (HR = 0.41, 95% CI: 0.27-0.62), while high expression of BAP1 was associated with poorer outcome in malignant pleural mesothelioma (HR = 2.03, 95% CI: 1.67-2.47). Our study revealed that BAP1 expression tends to have different prognostic values in different cancer types. Clinically, BAP1 may serve as a promising marker for prognostic prediction for certain cancer types.

PD-L1 expression associated with worse survival outcome in malignant pleural mesothelioma.

There is currently a need to identify prognostic biomarkers to assist in a risk adopted approach in treatment of malignant pleural mesothelioma (MPM). Expression of programmed death ligand 1 (PD-L1) has been studied as a prognostic biomarker in a number of tumors given its central role in antitumoral immune response evasion. Four previously published analyses found PD-L1 positivity to be an adverse survival prognostic factor in MPM. This study aims to further investigate the relationship between PD-L1 expression in mesothelioma tissues and survival outcome. Clinical data of MPM patients from a single institution between 2006 and 2016 were reviewed. Patient's archived tissues were stained with PD-L1 (Clone Ventana SP263). PD-L1 positivity was defined as>1% membranous staining regardless of intensity. Data from fifty eight patients were analyzed. Median age was 73, majority was male (49, 84%) and had ECOG between 0 and 2 (46, 79%). Most common histopathological subtype was epithelioid (42, 72%), 9 (16%) biphasic subtype and 7 (12%) sarcomatoid. Thirty one patients (53%) received best supportive care and twenty seven patients (47%) received chemotherapy or combination treatment. Forty-two patients had positive PD-L1 expression (72.4%). The median survival time for PD-L1 negative group is 15.5 months and 6 months for the positive group. Positive PD-L1 expression is independently correlated with worse prognosis (HR=2.02; 95% CI, 1.005-4.057; P-value=0.0484). Our analysis found a higher percentage of MPM patients with positive PD-L1 (>1%) compared to other studies. Highly positive PD-L1 expression was associated with statistically significantly lower median survival time.

1620P - Outcomes of malignant pleural mesothelioma (MPM) patients (p) treated with immune-oncology drugs (IO) in clinical trials

1620P - Outcomes of malignant pleural mesothelioma (MPM) patients (p) treated with immune-oncology drugs (IO) in clinical trials

P3.03-061 Burden of Disease and Management of Mesothelioma in France: A National Cohort Analysis: Topic: Mesothelioma Clinical

Malignant pleural mesothelioma (MPM) is an uncommon cancer with poor survival. The aim of this study was to determine the burden of MPM disease in France and analyze associations between socio-economic deprivation, population density, management and outcomes of MPM. We used a national hospital data base (PMSI-MCO) to extracted MPM incidents patients of years 2011 and 2012 (ICD-10 codes C45.0 and C54.9 as principal/related or significantly associated diagnosis (PD,RD, SAD) in 2011 and 2012, without MPM codes or C34/C38.4 codes as PD/RD/SAD since 2006). Patients were followed for two years after the initial diagnosis. Cox models were used to analysis one and two-years survival according to sex, age, comorbidities, management, a population density index (PDI) and a social deprivation index (SDI) based on census data aggregated at the municipalities level. 1890 patients were included on the analysis (men: 76%, age: 73.6 ± 10 years, significant comorbidities: 84%). Patients lived in urban zones in 57% cases and in highly deprived areas in 53%. Only 1% had a curative surgical procedure; 65% received at least one dose of chemotherapy (72% at least one administration of chemotherapy with pemetrexed, 28% at least one administration with pemetrexed - bevacizumab); 42% and 20% of the patient received chemotherapy on the last three and the last months of their life, respectively); Survival rate at one- and two-year were 64% and 48% respectively. In multi-variate analysis men, older, patients with chronic renale failure, patients with chronic respiratory failure and patients who didn't receive pemetrexed at any time of their management had worse prognostic. Adjusting analysis on age, gender, comorbidities (hypertension, diabetes, COPD), leaving in rural/semi-rural area was associated with a better survival at one and two-year, HR: 0.82 (0.72-0.96) and HR: 0.83 (0.73-0.94); social deprivation index was not a significant variable for survival. The mean cost management per patient was 27 624 ± (15894 ) euros (31.4% of this cost was the cost of pemetrexed and bevacizumab). MPM remained an uncommon disease, with less of 1000 new cases a year in France, with a very poor prognostic and a significant burden for National Health system.

P3.03-042 Study Comparing Volume and TNM in Predicting Clinical Outcome in Malignant Pleural Mesothelioma: Topic: Mesothelioma Clinical

Malignant pleural mesothelioma (MPM) is a rare cancer with relatively poor outcome. Only stage (TNM) and histotype can be considered prognostic factors, but TNM still results inaccurate and difficult to be classified. Several studies investigated the use of tumor volume (TV) for response assessment, but its role as predictor of survival is unclear. A cut-off of 600 cm3 seemed to divide patients (pts) with different prognosis. Our objective is to assess the association between baseline TV, stage/TNM and overall survival (OS). We retrospectively selected 49 MPM pts treated from August 2002 to January 2012. All pts had a digitally available baseline chest computed tomography (CT), performed before any treatment and up to 3 months after histological diagnosis. CT staging was carried out by two thoracic radiologists according to TNM staging system (7th Edition). Pleural disease volume measurements were obtained by a computer system. Major prognostic variables (age, sex, histology, TV, stage/TNM, treatment) were collected. Pts were divided in 2 groups according to baseline TV (large volume >600cm3; small volume <=600cm3). Association of volume groups, stage, T, N, M separately and OS was tested using Cox models adjusted by age, sex, histology and surgery. Thirty-three pts were men, 16 women; median age was 62 years (range 25-78). Forty pts had epithelioid MPM, 7 mixed histology, 2 unknown histology. Four pts were diagnosed in early stage (I-II) and 45 in advanced stage (III-IV). The mean baseline TV was 494.15 cm3 (range 17.91- 2,329.03). Pts with small volume had a slight but not statistically significant tendency to survive longer than pts with large volume (3-year OS=32% vs 21%, respectively). The HR was 1.5 (95% CI=0.6-3.7) for large volume pts, 4.3 (p=0.08;95%CI=0.8-22.1) and 7.5 (p=0.02; 95% CI=1.4-39.9) for stage III and IV, 7.0 (p=0.001; 95% CI=2.3-21) and 5.4 (p=0.005; 95% CI=1.7-17.4) for T3 and T4, respectively. Regarding N and M, not statistically significant results were observed. Coherently with the available literature, we report an association between baseline TV and prognosis; however it seems weak and barely near to statistical significance. On the contrary, stage, in particular T3, showed a stronger association with prognosis. Considering the small sample and the wide 95% CI, our results should be interpreted with caution; nevertheless they open a critical question on the TV prognostic role and suggest a greater relevance of adjacent organs infiltration in predicting prognosis. Further collaborative studies are needed.

549P Prognostic factors and clinical outcomes of malignant pleural mesothelioma in a real world-setting: An Asian cohort

549P Prognostic factors and clinical outcomes of malignant pleural mesothelioma in a real world-setting: An Asian cohort

58P PDL1 expression associated with worse survival outcome in malignant pleural mesothelioma

58P PDL1 expression associated with worse survival outcome in malignant pleural mesothelioma

549P Prognostic factors and clinical outcomes of malignant pleural mesothelioma in a real world-setting: An Asian cohort

549P Prognostic factors and clinical outcomes of malignant pleural mesothelioma in a real world-setting: An Asian cohort

185P - Activation of Akt by Hypoxia Predicts Poor Outcome in Malignant Pleural Mesothelioma (MPM)

ABSTRACT Introduction The Phosphatidylinositol-3 kinase (PI3K)/Akt (PKB) pathway is activated in a wide range of tumour types, and plays a central role in cell survival. Recent evidence indicates that hypoxia induces upregulation of Akt and activation of the Akt/PKB pathway. Once activated, Akt phosphorylates a variety of downstream substrates, including FOXO3a, which decreases transcription of the pro-apoptotic factor Bim, facilitating cell survival. We have shown that nuclear phospho-Akt (pAkt) expression is associated with more advanced disease or poor prognosis in Non-Small Cell Lung Cancer and MPM. Carbonic Anhydrase (CA)-IX, a tumour-specific member of the carbonic anhydrase family, is a surrogate marker of hypoxia overexpressed in solid tumours. This study examines the expression of CA-IX and phosphorylated Akt (pAkt) in tumour samples from patients with MPM, correlating expression with established prognostic factors. The role of pAkt in the survival of MPM cell lines exposed to both normoxia and hypoxia was also examined with both PI3K and PI3k-mTOR inhibitors. Methods Tumour sections were stained using pAkt and CA-IX specific antibodies. The effect of hypoxia on pAkt, Akt and Bim expression in 4 MPM cell lines in the presence or absence of LY294002 (phosphatidylinositol-3-kinase inhibitor) was examined by Western blot. The percentage of apoptotic cells was also quantified in these cells using FACs and High-Content Analysis (HCA). Changes in subcellular localisation of pAkt and FOXO3a were quantified using HCA. The cells were also transfected with siRNAs to PDK1or DNA-PKcs (two kinases known to catalyse the phosphorylation of Akt) and the effect on pAkt expression was determined by Western blot. Results A positive association between CA-IX and pAkt staining implies intra-tumoural hypoxia may stimulate Akt phosphorylation. Multivariate analysis showed increased expression of nuclear pAkt was associated with poor survival. Hypoxia induced the activation of Akt in MPM cell lines resulting in changes in the subcellular localisation of pAkt and FOXO3a. A greater increase in the level of apoptosis was seen in cells treated with PI3K inhibitors under hypoxia. Conclusion pAkt plays an anti-apoptotic role in MPM and represents a potential therapeutic target particularly in hypoxic tumours. Disclosure All authors have declared no conflicts of interest.

Relationship between 18F-FDG uptake on positron emission tomography and molecular biology in malignant pleural mesothelioma

BackgroundThe usefulness of 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography (PET) can help for predicting the therapeutic response and outcome in malignant pleural mesothelioma (MPM). However, no satisfactory biologic explanation exists for this phenomenon. The aim of this study is to investigate the underlying biologic mechanisms of 18F-FDG uptake. MethodsTwenty-one patients with MPM who underwent 18F-FDG PET before treatment were included in this study. Tumour sections were stained by immunohistochemistry for glucose transporter 1 (Glut1); glucose transporter 3 (Glut3); hypoxia-inducible factor-1 alpha (HIF-1α); hexokinase I; vascular endothelial growth factor (VEGF); microvessels (CD34); epidermal growth factor receptor (EGFR); cell proliferation (Ki-67 labelling index); Akt/mTOR signalling pathway (PTEN, p-Akt, p-mTOR and p-S6K); cell cycle control (p53 and pRb); apoptosis marker (bcl-2). We also conducted an in vitro study of 18F-FDG uptake in mesothelioma cell lines. Results18F-FDG uptake was significantly correlated with Glut1 (p<0.0001), HIF-1α (p=0.006), hexokinase I (p=0.0002), VEGF (p=0.0013), CD34 (p=0.0001), Ki-67(p=0.0047), mTOR (p=0.00478) and p53 (p=0.0004). High uptake of 18F-FDG was significantly associated with poor outcome in MPM. Our in vitro study showed that upregulation of Glut1 and HIF-1α was closely related with 18F-FDG uptake into mesothelioma cell, and mTOR inhibitor induced a decrease in Glut1 expression and 18F-FDG uptake. ConclusionThe amount of 18F-FDG uptake in MPM is determined by the presence of glucose metabolism, phosphorylation of glucose, hypoxia, angiogenesis, cell proliferation (Ki-67), cell cycle regulator, and mTOR signalling pathway.

Soluble mesothelin, megakaryocyte potentiating factor, and osteopontin as markers of patient response and outcome in malignant pleural mesothelioma.

7086 Background: Radiological response evaluation is notoriously difficult in patients with malignant pleural mesothelioma, an asbestos-related malignancy. Soluble mesothelin (SM), megakaryocyte potentiating factor (MPF), and osteopontin (OPN) are blood biomarkers of mesothelioma. This study evaluates their use as markers of response to therapy and outcome. Methods: 62 patients with malignant pleural mesothelioma were surveilled in a Belgian observational multicenter study. Blood samples and CTs were collected at diagnosis and, when possible, during and after therapy, until disease progression or death. SM and MPF levels were measured in serum with the Mesomark ELISA and the non-commercial Human MPF ELISA, respectively. OPN levels were measured in plasma with the Human Osteopontin ELISA. For each patient, the best overall radiological response was compared with the change in serum SM, MPF and plasma OPN levels across the corresponding time points. Survival analysis was performed with Cox proportional hazard regression and log-rank statistics. Results: In five patients who underwent extrapleural pneumonectomy, SM and MPF markedly decreased after surgery, whereas OPN showed a median increase. Of the 57 patients who received chemotherapy, 27 (47%) had radiological stable disease (SD), 14 (25%) partial response (PR), and 16 (28%) progressive disease (PD). In patients with SD, biomarker levels did not change significantly (SM and MPF), or decreased (OPN). For PR and PD, biomarker levels typically decreased and increased, respectively. A change ≥15% in all three biomarkers significantly correlated with patient response, whereas SM and MPF appeared more accurate than OPN. Low baseline OPN levels were independently associated with favorable overall and progression free survival. Neither SM nor MPF were informative for patient outcome. Conclusions: Relative changes in SM, MPF and OPN all three correlated with disease course, whereas SM and MPF appeared most suitable for monitoring of patients with mesothelioma. Baseline OPN levels were an independent negative predictor of survival. Further validation of these promising results remains mandatory.

Improving the outcome in malignant pleural mesothelioma: nonaggressive or aggressive approach?

The treatment of malignant pleural mesothelioma continues to be a clinical challenge. The question, however, is no longer whether to provide active treatment or not, but how aggressive the treatment should be in view of the limited life expectancy of patients with this disease. With platin and pemetrexed-based combination chemotherapy having become the preferred systemic therapy, the major questions now evolve around the identification of a suitable second line therapy and the quest for innovative new approaches. Surgical interventions from pleurectomy and decortication to extrapleural pneumonectomy have increasingly come of use in specialized centres. With neoadjuvant chemotherapy and extrapleural pneumonectomy median survival times of almost 2 years have been reported. Studies on high-dose hemithoracic radiotherapy after extrapleural pneumonectomy suggested a beneficial effect on local recurrence. However, both extrapleural pneumonectomy and high-dose hemithoracic radiotherapy are associated with potential treatment-related mortality and morbidity and cannot yet be recommended outside specialized centres. More than ever, the diagnosis and treatment of patients with malignant pleural mesothelioma mandate a multidisciplinary approach.

Validation of Genomics-Based Prognostic Tests in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm with limited pretreatment prognostication strategies. In this report, we examine the accuracy of a previously proposed prognostic test in an independent cohort of MPM patients. This test uses simple ratios of gene expression levels to provide a novel prognostication scheme. Gene expression data using high-density oligonucleotide microarrays (approximately 22,000 genes) were obtained for a new cohort of human MPM tumors from patients undergoing similar treatments (n = 39). The relative expression levels for specific genes were also determined using real-time quantitative reverse transcription-PCR. We also used a subset of these tumors associated with widely divergent patient survival (n = 23) as a training set to identify new treatment-specific candidate prognostic molecular markers and gene ratio-based prognostic tests. The predictive nature of these newly discovered markers and gene ratio-based prognostic tests were then examined in an independent group of tumors (n = 52) using microarray data and quantitative reverse transcription-PCR. Previously described MPM prognostic genes and gene ratio-based prognostic tests predicted clinical outcome in 39 independent MPM tumor specimens in a statistically significant manner. Newly discovered treatment-specific prognostic genes and gene ratio-based prognostic tests were highly accurate and statistically significant when examined in an independent group of 52 tumors from patients undergoing similar treatment. The data support the use of gene ratios in translating gene expression data into easily reproducible, statistically validated clinical tests for the prediction of outcome in MPM.