Biomarker For Malignant Mesothelioma Research Articles

Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress.

Malignant mesothelioma (MM) is a rare and aggressive neoplasm, usually associated with a poor prognosis (5 years survival rate <10%). For unresectable disease, platinum and pemetrexed chemotherapy has been the only standard of care in first line for more than two decades, while no standard treatments have been approved in subsequent lines. Recently, immunotherapy has revolutionized the therapeutic landscape of MM. In fact, the combination of ipilimumab plus nivolumab has been approved in first line setting. Moreover, immune checkpoint inhibitors (ICIs) showed promising results also in second-third line setting after platinum-based chemotherapy. Unfortunately, approximately 20% of patients are primary refractory to ICIs and there is an urgent need for reliable biomarkers to improve patient's selection. Several biological and molecular features have been studied for this goal. In particular, histological subtype (recognized as prognostic factor for MM and predictive factor for chemotherapy response), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (widely hypothesized as predictive biomarkers for ICIs in several solid tumors) have been evaluated, but with unconclusive results. On the other hand, the deep analysis of tumor infiltrating microenvironment and the improvement in genomic profiling techniques has led to a better knowledge of several mechanisms underlying the MM biology and a greater or poorer immune activation. Consequentially, several potential biomarkers predictive of response to immunotherapy in patients with MM have been identified, also if all these elements need to be further investigated and prospectively validated. In this paper, the main evidences about clinical efficacy of ICIs in MM and the literature data about the most promising predictive biomarkers to immunotherapy are reviewed.

Serum Calretinin as a Biomarker in Malignant Mesothelioma.

The early diagnosis of malignant mesothelioma (MM) could improve the prognosis of MM patients. To confirm an MM diagnosis, an immunohistochemical analysis of several tumor tissue markers, including calretinin, is currently required. Our aim is to evaluate serum calretinin as a potential biomarker in asbestos-related diseases, especially in MM. Our study includes 549 subjects: 164 MM patients, 117 subjects with asbestosis, 195 subjects with pleural plaques and 73 occupationally asbestos-exposed subjects without asbestos-related diseases. The serum calretinin concentration was determined with a commercially available enzyme immunoassay. Data on the soluble mesothelin-related peptides (SMRP) concentration are available from previous studies. MM patients had a significantly higher calretinin concentration than subjects without disease, subjects with pleural plaques or subjects with asbestosis (all p < 0.001). The histological type was significantly associated with serum calretinin: patients with sarcomatoid MM had lower calretinin than patients with the epithelioid type (p = 0.001). In a ROC curve analysis, the area under the curve for calretinin concentration predicting MM was 0.826 (95% CI = 0.782–0.869; p < 0.001). At the cutoff value of 0.32 ng/mL, sensitivity was 0.683, while specificity was 0.886. The combination of calretinin and SMRP had the highest predictive value. Calretinin is a useful biomarker that can distinguish MM from other asbestos-related diseases and could, therefore, contribute to an earlier non-invasive diagnosis of MM.

Abstract 1382: Megakaryocyte potentiating factor as a predictive biomarker for therapies against malignant mesothelioma

Abstract Objectives: Effective biomarkers for malignant mesothelioma (MM) are needed for clinical management and the development of cell surface mesothelin-targeted therapies. We evaluated serum megakaryocyte potentiating factor (MPF) as a biomarker predictive of clinical outcome in MM patients, for patient monitoring, and for developing mesothelin-targeted therapies. Patients and Methods: Serial serum samples from MM patients in two clinical trials of an anti-mesothelin immunotoxin were tested for serum MPF. For the purpose, we developed a new MPF assay and conducted both analytical and clinical validation. Correlative studies were performed to determine the test effectiveness in treatment monitoring and outcome prediction. MPF was further evaluated for an association with response to an anti-mesothelin therapy and for disease monitoring. Results: Our data showed that in MM patients, elevated serum MPF is a predictor of poor survival with a hazard ratio (HR) = 2.46 (Log Rank P = 0.003; n = 95). In refractory MM patients, elevated MPF is a strong predictor of poor outcome with a HR = 6.12 (Log Rank P = 0.0007; n = 57). There was a significant reduction of serum MPF in patients with elevated baseline and radiological response, with an average change from -52% to -78% after 1 to 6 cycles. Using a -50% change as the cutoff, MM patients with a positive MPF-response had significantly improved progression-free survival (PFS) (P &amp;lt; 0.0001), with median extended from 1.9 to 11.3 months. These MPF-response patients further exhibited improved overall survival (OS) (P = 0.004), with median extended from 8.8 to 22.3 months. In refractory MM patients, there was an association between elevated pre-treatment serum MPF and radiological response to an experimental anti-mesothelin therapy (P = 0.033). Furthermore, in these response patients, serum MPF was monitored between 32.2 and 63.8 months and found to reflect the response and disease progression. Conclusion: In MM patients, elevated MPF was observed in 2/3rd of the patients and is a predictor for poor survival, throughout the course of the disease. Following systemic therapies, a &amp;gt; -50% reduction in MPF was associated with improved clinical outcome, both PFS and OS. An elevated baseline serum MPF may be a predictor of response to an experimental anti-mesothelin therapy in refractory MM patients, however, the finding needs to be confirmed in a larger study. Citation Format: Liang Cao, Yunkai Yu, Anish. Thomas, Jingli Zhang, Masanori Onda, Paul Meltzer, Raffit Hassan, Ira Pastan. Megakaryocyte potentiating factor as a predictive biomarker for therapies against malignant mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1382.

Fibulin-3 as biomarker of malignant mesothelioma.

Many malignant diseases are associated with past asbestos exposure; the most lethal and strictly related to previous fiber exposure being malignant mesothelioma (MM). Effective preventive protocols may include sensitive and specific biomarkers. The role of Fb-3 has been recently investigated for MM early detection, but its role is still under debate. After an independent search for scientific literature, nine studies were included for a systematic review.Human Fb-3 levels seem to be able to separate healthy people with previous exposure to asbestiform fibers from MM patients. Fb-3 blood levels can distinguish MM effusions from other malignant and benign effusions. Furthers investigations on more significant groups of patients are desirable to validate and assess the validity of combining Fb-3 with other biomarkers.

Analysis of fibulin-3 after exposure to asbestos-like fibers

A significantly increased incidence of malignant mesothelioma in Biancavilla (Sicily, Italy) has been ascribed to exposure to fluoro-edenite, a fibrous amphibole extracted from a local stone quarry. Fibulin-3 is a highly conserved glycoprotein proposed as a biomarker for malignant mesothelioma that belongs to the family of extracellular matrix proteins. Previous studies demonstrated high Fibulin-3 plasma levels in workers with pleural plaques exposed to fluoro-edenite.Therefore, in order to gain insight into the biomolecular mechanisms of fluoro-edenite toxicity, we performed the analysis of Fibulin-3 expression by immunohistochemistry in the lung samples derived from sheep belonging to the area of Biancavilla. Furthermore, an in vitro model of exposed fluoro-edenite fibroblasts was used to perform functional experiments to better understand the modulation of Fibulin-3 expression. The percentage of immunostained area by Fibulin-3 was very much higher in exposed lungs compared with non-exposed ones. The Fibulin-3 protein level was significantly expressed in primary human lung fibroblasts exposed to 50 and 100µg/ml of fluoro-edenite fibers for 72h, compared to the unexposed controls. The results from the present study further demonstrate the implication of Fibulin-3 during fluoro-edenite exposure. This would endorse our previous results regarding the use of Fibulin-3 as a possible screening biomarker for fluoro-edenite exposed individuals, thereby contributing to the monitoring of the population at risk. The present study also suggested that the Fibulin-3 overexpression may reflect a defensive response of the tissues after exogenous stimuli and may be implicated in cancer development, especially in the context of fluoro-edenite contamination. However, further studies are necessary in order to make Fibulin-3 a customized screening tool.

P3.03-009 Role of microRNAs as Biomarkers of Malignant Mesothelioma in Patients with Pleural Effusion: Topic: Mesothelioma Transitional

Pleural effusion (PE) is a common clinical presentation of a large number of different diseases including malignant pleural mesothelioma (MPM). The approach to patients with PE is not simple and pre-operative cytological examinations or even intra-operative frozen sections are often unhelpful in the differential diagnosis. This fact makes critical the management of PE, especially when MPM is suspected. Changes in the expression of microRNAs (miRNAs) have been implicated in several diseases, making miRNAs attractive biomarkers. Our aim was to determine whether a miRNA signature in plasma or in Exhaled Breath Condensate (EBC) may help to discriminate between PE related to MPM and PE of patients affected by other pleural diseases (NM). We prospectively enrolled consecutive patients with PE from suspected MPM, scheduled for thoracoscopic pleural biopsy. We recorded clinical data and definitive histological diagnosis. Exclusion criteria were age < 18 years, history of previous tumor or immunological disorder. Ethics committee approval was achieved. Written informed consent was obtained from all participants. We collected a sample of plasma and EBC from each patient before the biopsy. We screened 733 miRNAs in blood and EBC by high-throughput Open Array and compared their expression in the two groups. We used a multiple linear regression model adjusted for four principal variables (age, sex, BMI and smoking habits) to compare MPM and NM. We enrolled 32 patients; the figure below shows main clinical data. After miRNA screening, we identified 3 miRNAs which were upregulated in EBC and 44 in plasma. In particular, in EBC: miR-378, miR-206, miR-9 with a fold-change (FC) of 1.54, 1.4, 1.23 respectively (p-value= 0.019, 0.04 and 0.04 respectively). The most significant in plasma was miR-489 (FC= 1.35, p-value= 0.0001). We identified a miRNAs panel that might be useful for developing a non-invasive procedure for MPM diagnosis in patients with PE.

Glycodelin is a potential novel follow-up biomarker for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor with a short survival time arising from the mesothelial cells of the pleura. Soluble mesothelin-related peptide (SMRP), osteopontin or EFEMP1 (Fibulin-3) are well described biomarkers for malignant mesothelioma with moderate sensitivity and specificity. In this study, we characterized the expression of glycodelin, a marker for risk pregnancy, in MPM by RNA and protein analyses and investigated its potential as a MPM biomarker. We were able to detect glycodelin in the serum of MPM patients. Compared to benign lung diseases, the serum levels were significant increased. Patients with high glycodelin serum levels revealed a worse overall survival. The glycodelin serum levels correlated with the tumor response to treatment. A comparison of SMRP and glycodelin serum measurement in a large patient cohort demonstrated that the detection of both soluble factors can increase the reliable diagnostic of MPM. Glycodelin was highly expressed in MPM tumors. Analyses of a tissue micro array indicated that the immunomodulatory form glycodelin A was expressed in MPM and correlated with the survival of the patients. Altogether, glycodelin seems to be a new potential biomarker for the aggressive malignant pleural mesothelioma.

FBLN-3 as a biomarker of pleural plaques in workers occupationally exposed to carcinogenic fibers: a pilot study.

FBLN-3 has recently been proposed as a biomarker for malignant mesothelioma. A significantly increased standardized mortality rate from malignant mesothelioma has been reported in Biancavilla, Italy. Its cause has been identified in environmental exposure to fluoro-edenite. The aim of this study was to seek a correlation between plasma FBLN-3 concentration and pleural plaques in subjects exposed to fluoro-edenite and in a nonexposed control group. Pleural plaques was never detected in the control group, whereas it was found in 52% of exposed subjects. Median FBLN-3 concentrations were 12.96 and 5.29 ng/ml in the exposed and the control group, respectively (p < 0.001). FBLN-3 plasma levels exhibited a high predictive value for the presence of pleural plaques.

ERCC1 and Thymidylate Synthase as Prognostic Biomarkers in Malignant Mesothelioma

The standard of care for malignant pleural mesothelioma (MPM) is a combination of platinum compounds and Pemetrexed. Still, the median survival of MPM patients is low (about 12 months). Excision Repair Cross Complementing Group 1 (ERCC1) acts by removing DNA adducts formed by platinum compounds, whereas Pemetrexed inhibits Thymidylate Synthase (TS), which is involved in DNA synthesis.Pleural biopsies were collected from 140 MPM patients (98 males and 42 females, mean age 68 years) before treatment initiation. Average disease specific survival was 13 months (range 1‐60). mRNA was extracted from formalin fixed paraffin blocks, reverse transcribed and assayed by qRT‐PCR. Immunohistochemistry with anti‐ERCC1 and anti‐TS mAbs was scored semi‐quantitatively.Of 140 patients, 102 were treated, the remaining were not because of bad performance status or advanced age. Patients with low ERCC1 protein expression survived longer (24.3 vs 12.5 months, P=.03). Likewise, patients with low levels of TS mRNA had better survival (P=.01); there was no advantage, however, in the treated sub‐group, suggesting that Pemetrexed treatment and low TS expression had no additive value.ERCC1 protein expression and TS gene expression both seem important prognostic markers; we suggest their evaluation in routine biopsies from MPM patients.

Research progress on biomarkers of malignant mesothelioma

恶性间皮瘤(malignant mesothelioma,MM)是源自间皮细胞的恶性肿瘤,可发生于胸膜的任何部位,也有少数发生于腹膜、心包膜、输卵管浆膜、睾丸鞘膜等.多呈隐袭性起源,其发病率占全部肿瘤的0.02％～0.4％,其中90％起源于胸膜,6％～10％起源于腹膜[1].石棉被认为是MM的首要致病因素,国际公认约80％的MM病例与职业或环境中接触石棉有关.该病临床表现不典型,早期诊断困难,目前尚无有效治疗措施,病死率高,预后差,一般中位生存期不超过1年[2].近年,一些地区的MM发病率有明显增加的趋势,可能与过去数十年中石棉材料的生产使用有关,愈来愈引起人们的关注.鉴于某些生物标志对准确发现MM早期病变,了解病变进展,指导治疗,并为判断预后有着重要作用,我们对MM诊疗相关的生物标志进行综述,以期为临床提供更多的信息。

Attempted Validation of Surface Enhanced Laser Desorption Ionization-Time of Flight Derived Kinesin Biomarkers in Malignant Mesothelioma

Surface-enhanced Laser Desorption/Ionization Time-of-flight (SELDI-TOF) mass spectrometry allows researchers to search proteomes for biomarkers of disease. Validating SELDI-TOF results using traditional methodologies has yielded mixed results. Real-time PCR, ELISA and Western blot assays were utilized in an attempt to confirm the link between asbestos related cancers and kinesin family proteins, KIF5A and KIF18A. These proteins had been identified using SELDI-TOF and Classification and Regression Tree Analysis (CART) in serum of patients with asbestos related cancers. When well-characterized asbestos fibers were used to challenge mesothelial cell lines, mixed results in KIF5A and KIF18A RNA expression were observed. Western blot analysis comparing protein levels in mesothelioma cell lines versus transformed mesothelial cells yielded inconclusive results, as did Western blot analyses of human mesothelioma and non-cancerous peritoneum that had been obtained from the same patients. These results suggest that kinesin family proteins detected by SELDI-TOF CART are unlikely to be of use as biomarkers for malignant mesothelioma.

Increased Circulating miR-625-3p: A Potential Biomarker for Patients With Malignant Pleural Mesothelioma

We investigated the ability of cell-free microRNAs (miRNAs) in plasma and serum to serve as a biomarker for malignant mesothelioma (MM). Using miRNA microarrays, we profiled plasma samples from MM patients and healthy controls. miRNAs with significantly different abundance between cases and controls were validated in a larger series of MM patients and in an independent series of MM patients using quantitative real-time polymerase chain reaction. Levels of candidate miRNAs were also quantified in MM tumor samples. We compared cell-free miRNA profiles in plasma from MM patients with healthy controls. Reviewing 90 miRNAs previously reported to be associated with MM, we found that the levels of two miRNAs, miR-29c* and miR-92a, were elevated in plasma samples from MM patients. In addition, we identified 15 novel miRNAs present at significantly higher levels in the plasma of MM patients. Further analysis of candidate miRNAs by real time-quantitative polymerase chain reaction confirmed that one of them, miR-625-3p, was present in significantly higher concentration in plasma/serum from MM patients and was able to discriminate between cases and controls, in both the original and the independent series of patients. MiR-625-3p was also found to be up-regulated in tumor specimens from a group of 18 MM patients, who underwent extrapleural pneumonectomy. Our data confirm the potential of miR-29c* and miR-92a as candidate tumor markers and reveal that miR-625-3p is a promising novel diagnostic marker for MM.

PP 15 BRCA1 expression is required for efficacy of vinorelbine and is a predictive biomarker in malignant mesothelioma

PP 15 BRCA1 expression is required for efficacy of vinorelbine and is a predictive biomarker in malignant mesothelioma

Biomarkers in Malignant Mesothelioma: Diagnostic and Prognostic Role of Soluble Mesothelin-Related Peptide

Soluble mesothelin-related peptide (SMRP) is a biomarker that has been proposed for differential diagnosis from pleural metastatic cancer, as well as prognosis and treatment monitoring of malignant pleural mesothelioma (MM). The aim of this study was to evaluate the role of SMRP in clinic management of MM. We assayed the SMRP concentrations in 354 subjects: 109 healthy volunteers with no history of exposure to asbestos, 26 patients with previous occupational asbestos exposure but who were free from pleural or parenchymal disease, 48 patients with asbestosis, 110 patients with pleural plaques, 25 patients with lung cancer, and 36 patients with MM. We also tested SMRP titers in 2 patients with MM at 5 different times of the disease, to evaluate the trend of the biomarker in the course of therapy. Our data confirm previous experiences with the use of SMRP as a diagnostic marker of MM. Low SMRP levels at diagnosis seem to have a positive prognostic significance.

Molecular biomarkers in malignant mesothelioma: state of the art

Malignant mesothelioma (MM) is an aggressive tumour affecting the mesothelial surfaces of the pleural and peritoneal cavities and, rarely, the pericardium and the tunica vaginalis testis. Despite a ban of asbestos in many industrialised nations, the present high incidence of MM is expected to continue, due to the long latency period between first asbestos exposure and occurrence of disease, making it an important health issue for the future. The diagnosis of MM can be difficult, both from a clinical and pathological perspective. It is not unusual for patients to undergo several medical investigations without definitive diagnosis early in their course of illness. Understandably, there is intense interest in the discovery of markers that can be assessed in pleural effusions, histological specimens, and serum to assist with the difficult early diagnosis of MM. Considering the primary aetiological role of asbestos, there is theoretically an easily identifiable target population for screening with a biomarker with adequate sensitivity and specificity or with a combination of biomarkers. In this review we focus on biomarkers that have been examined in the setting of either early diagnosis of MM in symptomatic patients or screening of asbestos-exposed individuals.

156 Soluble mesothelin-related protein (SMRP) is a useful biomarker for malignant mesothelioma in Japan

156 Soluble mesothelin-related protein (SMRP) is a useful biomarker for malignant mesothelioma in Japan