Evolving Landscape of Initial Treatments for Patients with Malignant Pleural Mesotheliomas: Clinical Trials to Clinical Practice.
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ABSTRACT:
SUBMITTER: Offin M
PROVIDER: S-EPMC9355824 | biostudies-literature | 2022 Aug
REPOSITORIES: biostudies-literature
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Evolving Landscape of Initial Treatments for Patients with Malignant Pleural Mesotheliomas: Clinical Trials to Clinical Practice.
Offin Michael M Rusch Valerie W VW Rimner Andreas A Adusumilli Prasad S PS Zauderer Marjorie G MG
The oncologist 20220801 8
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Project description:Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy that most commonly affects the pleural lining of the lungs. It has a strong association with exposure to biopersistent fibers, mainly asbestos (80% of cases) and-in specific geographic regions-erionite, zeolites, ophiolites, and fluoro-edenite. Individuals with a chronic exposure to asbestos generally have a long latency with no or few symptoms. Then, when patients do become symptomatic, they present with advanced disease and a worse overall survival (about 13/15 months). The fibers from industrial production not only pose a substantial risk to workers, but also to their relatives and to the surrounding community. Modern targeted therapies that have shown benefit in other human tumors have thus far failed in MPM. Overall, MPM has been listed as orphan disease by the European Union. However, molecular high-throughput profiling is currently unveiling novel biomarkers and actionable targets. We here discuss the natural evolution, mainly focusing on the novel concept of molecular epidemiology. The application of innovative endpoints, quantification of genetic damages, and definition of genetic susceptibility are reviewed, with the ultimate goal to point out new tools for screening of exposed subject and for designing more efficient diagnostic and therapeutic strategies.
| S-EPMC7959144 | biostudies-literature
Project description:In this article, we review ongoing novel clinical trials currently investigating immunotherapeutic approaches for patients with malignant pleural mesothelioma (MPM). There is a dearth of effective therapeutic options for patients diagnosed with MPM and metastatic cancers of the pleura; these diseases have an estimated annual incidence of 150,000. Modulating the immune microenvironment to promote antitumor immune responses by systemically and regionally delivered therapeutic agents is an active area of investigation. We have conducted a review of the clinical trials database for clinical trials actively recruiting MPM patients. We focused on novel therapeutic agents administered either systemically or intrapleurally to modulate the tumor immune microenvironment. Herein, we have summarized the published results of early phase clinical trials. A total of 43 clinical trials met our inclusion criteria. These trials are investigating immunologic agents (n=20) and antibody directed therapies (n=23). The regional intrapleural delivery technique (6 trials) is used to administer chemotherapy agents (3 of 6 trials) and immunotherapy agents (3 of 6 trials), including chimeric antigen receptor T cells (1 of 6 trials). Current clinical trials modulating the MPM immune microenvironment and the combination of these novel agents with standard of care therapy provide a promising area of investigation for MPM therapy.
| S-EPMC5497103 | biostudies-literature
Project description:IntroductionAlthough next-generation sequencing (NGS) has brought insight into critical mutations or pathways (e.g., DNA damage sensing and repair) involved in the etiology of many cancers and has directed new screening, prevention, and therapeutic approaches for patients and families, it has only recently been used in malignant pleural mesotheliomas (MPMs).MethodsWe analyzed the blood samples from patients with MPM using the NGS platform MSK-IMPACT to explore cancer-predisposing genes. The loss-of-function variants or pathogenic entries were identified, and clinicopathologic information was collected.ResultsOf 84 patients with MPM, 12% (10 of 84) had pathogenic variants. Clinical characteristics were similar between cohorts, although patients with germline pathogenic variants were more likely to have more than two first-degree family members with cancer than those without germline mutations (40% versus 12%; Fisher's exact test, p < 0.05). Novel, deleterious variants in mesotheliomas included MutS homolog 3 (1% [one of 84]; 95% confidence interval [CI]: 0%-7%), breast cancer gene 1-associated ring domain 1 (1% [one of 84]; 95% CI: 0%-7%), and RecQ-like helicase 4 (2% [two of 84]; 95% CI: 0%-9%). Pathogenic variants previously reported on germline testing in patients with mesotheliomas were breast cancer gene 1-associated protein 1 (4% [three of 84]; 95% CI: 1%-10%), breast cancer gene 2 (1% [one of 84]; 95% CI: 0%-7%), and MRE11 homolog, double strand break repair nuclease (1% [one of 84]; 95% CI: 0%-7%). One patient (1% [one of 84]; 95% CI: 0%-7%) had a likely pathogenic alteration in SHQ1, H/ACA ribonucleoprotein assembly factor that has not been associated with a heritable susceptibility to cancer.ConclusionsOur study lends further support for the role of aberrations in DNA damage repair genes in the pathogenesis of MPMs and suggests that targeting the members of these pathways for screening and treatment warrants further study.
| S-EPMC7526793 | biostudies-literature
Project description:In this commentary, using existing clinical trial data and FDA approvals we propose that there is currently a critical need for an appropriate balancing between the financial impact of new cancer drugs and their actual benefit for patients. By adopting "pleural mesothelioma" as our clinical model we summarize the most relevant pertinent and available literature on this topic, and use an analysis of the reliability of the trials submitted for registration and/or recently published as a case in point to raise concerns with respect to appropriate trial design, biomarker based stratification and to highlight the ongoing need for balancing the benefit/cost ratio for both patients and healthcare providers.
| S-EPMC9749371 | biostudies-literature
Project description:Malignant mesothelioma (MM) is a therapy-resistant cancer arising primarily from the lining of the pleural and peritoneal cavities. The most frequently altered genes in human MM are cyclin-dependent kinase inhibitor 2A (CDKN2A), which encodes components of the p53 (p14ARF) and RB (p16INK4A) pathways, BRCA1-associated protein 1 (BAP1), and neurofibromatosis 2 (NF2). Furthermore, the p53 gene (TP53) itself is mutated in ~15% of MMs. In many MMs, the PI3K-PTEN-AKT-mTOR signaling node is hyperactivated, which contributes to tumor cell survival and therapeutic resistance. Here, we demonstrate that the inactivation of both Tp53 and Pten in the mouse mesothelium is sufficient to rapidly drive aggressive MMs. PtenL/L ;Tp53L/L mice injected intraperitoneally or intrapleurally with adenovirus-expressing Cre recombinase developed high rates of peritoneal and pleural MMs (92% of mice with a median latency of 9.4 weeks and 56% of mice with a median latency of 19.3 weeks, respectively). MM cells from these mice showed consistent activation of Akt-mTor signaling, chromosome breakage or aneuploidy, and upregulation of Myc; occasional downregulation of Bap1 was also observed. Collectively, these findings suggest that when Pten and Tp53 are lost in combination in mesothelial cells, DNA damage is not adequately repaired and genomic instability is widespread, whereas the activation of Akt due to Pten loss protects genomically damaged cells from apoptosis, thereby increasing the likelihood of tumor formation. Additionally, the mining of an online dataset (The Cancer Genome Atlas) revealed codeletions of PTEN and TP53 and/or CDKN2A/p14ARF in ~25% of human MMs, indicating that cooperative losses of these genes contribute to the development of a significant proportion of these aggressive neoplasms and suggesting key target pathways for therapeutic intervention.
| S-EPMC6168364 | biostudies-literature
Project description:Purpose To provide evidence-based recommendations to practicing physicians and others on the management of malignant pleural mesothelioma. Methods ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, pathology, imaging, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 1990 through 2017. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. Results The literature search identified 222 relevant studies to inform the evidence base for this guideline. Recommendations Evidence-based recommendations were developed for diagnosis, staging, chemotherapy, surgical cytoreduction, radiation therapy, and multimodality therapy in patients with malignant pleural mesothelioma. Additional information is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki .
| S-EPMC8058628 | biostudies-literature
Project description:Compare the global methylation profile of 20 malignant pleural mesotheliomas and lung adenocarcinomas. A DNA mixture of two normal mesothelium tissues was used as a reference for the mesotheliomas and a mixture of five normal lung tissues used as the reference for the lung adenocarcinomas
2009-12-01 | E-TABM-813 | biostudies-arrayexpress
Project description:ImportanceSome recently proposed frontline therapies for malignant pleural mesothelioma (MPM) are very costly, yet their impact on quality of life and overall survival of these patients remains arguable. Given the high social toll of this aggressive occupational cancer, it is paramount to establish the real clinical benefit of these treatments.ObjectiveTo directly compare and analyze the statistical robustness of the 3 randomized clinical trials (RCTs) of frontline therapies recommended for MPM since 2003.Design, setting, and participantsThis comparative effectiveness study assessed the following phase 3 RCTs: the Mesothelioma Cisplatin Pemetrexed Study (MPS) of cisplatin plus pemetrexed vs cisplatin; the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) of cisplatin plus pemetrexed plus bevacizumab vs cisplatin plus pemetrexed; and the CheckMate743 (CM743) study of nivolumab plus ipilimumab vs cisplatin plus pemetrexed. Data collection dates for the RCTs ranged from April 1999 to April 2018. Data for this study were analyzed from February to October 2021.Main outcomes and measuresPatient selection criteria, superiority of the intervention groups, survival-inferred fragility index, and censoring patterns in each RCT.ResultsA total of 1501 patients were included in the analysis (1170 men [77.9%]; range of median age for treatment groups, 60 [IQR, 19-84] to 69 [IQR, 65-75] years). A virtual comparison of overall survival in MAPS vs the CM743 study showed no statistically significant difference (hazard ratio [HR], 0.97 [95% CI, 0.79-1.20]; P = .79), and the survival-inferred fragility index in the intention-to-treat (ITT) populations was as low as 0.22% of the total sample size in MPS, -0.45% of the total sample size in MAPS, and 0.99% of the total sample size in the CM743 trial. Moreover, reverse restricted mean survival time (RMST) analysis of overall survival using RMST-difference (RMST-D) demonstrated differential censoring in the ITT population of the CM743 trial favoring the control group (0.56 [95% CI, 0.18-0.94]; P = .004) and in the nonepithelioid group (reverse RMST-D, 0.90 [95% CI, 0.001-1.79]; P = .048).Conclusions and relevanceThis comparative effectiveness study found no survival benefit in the CM743 trial over MAPS, despite the inclusion of patients with worse prognosis in the latter trial. Moreover, the statistical conclusions of all the examined trials were shown to be extremely fragile, and the findings of differential censoring in the CM743 trial and in the ITT nonepithelial subset raised additional areas of concern. These findings suggest that selection criteria, fragility, and censoring patterns may affect the original conclusions drawn for the respective trials, casting a shadow on the real benefit. This model of analysis lays a rigorous groundwork extendable to trials of all cancer treatments before their registration.
| S-EPMC8908075 | biostudies-literature
Project description:Malignant pleural mesothelioma (MPM) is a rare cancer usually caused by asbestos exposure and associated with a very poor prognosis. After more than a decade without new therapeutic options, immune checkpoint inhibitors (ICIs) demonstrated superiority over standard chemotherapy, with improved overall survival in the first and later-line settings. However, a significant proportion of patients still do not derive benefit from ICIs, highlighting the need for new treatment strategies and predictive biomarkers of response. Combinations with chemo-immunotherapy or ICIs and anti-VEGF are currently being evaluated in clinical trials and might change the standard of care in the near future. Alternatively, some non-ICI immunotherapeutic approaches, such as mesothelin targeted CAR-T cells or denditric-cells vaccines, have shown promising results in early phases of trials and are still in development. Finally, immunotherapy with ICIs is also being evaluated in the peri-operative setting, in the minority of patients presenting with resectable disease. The goal of this review is to discuss the current role of immunotherapy in the management of malignant pleural mesothelioma, as well as promising future therapeutic directions.
| S-EPMC10003250 | biostudies-literature
Project description:BackgroundMesothelioma is a rare and aggressive malignant neoplasm arising from mesothelial cells, which occasionally manifests recurrent fusions. EWSR1/FUS-CREB, YY1, MAP3K8, NR4A3, and ALK-rearranged proliferations have been reported in limited series with no clear histological or clinical correlations, limiting clinicians' ability to assess prognosis and integrate these new entities into therapeutic decisions. The aim of this study was to better characterize these rearranged proliferations histologically, molecularly, and clinically.MethodsClinical, pathological, and comprehensive transcriptome and mutation data were collected for each case.ResultsA total of 41 tumors were included, encompassing 7 ALK, 10 MAP3K8, 4 NR4A3, 8 ESWR1/FUS::ATF1, 8 EWSR1::YY1, and 4 SUFU-fused cases. We found a female predominance, except for cases harboring NR4A3 and SUFU; and most patients were around 60 years of age, but those harboring ALK or EWSR1/FUS::ATF1 gene fusions were younger. Each group exhibited distinct histological, immunohistochemical, molecular features, and oncological courses. Specifically, MAP3K8 and ALK presented PAX8+ papillary proliferations, ESWR1/FUS::ATF1 and EWSR1::YY1 displayed angiomatoid fibrous histiocytoma-like patterns, while SUFU showcased 'tissue culture'-like spindle cell proliferation. Poor prognosis factors were the pleural site, male sex, Ki67 ≥10%, and ESWR1/FUS::ATF1 or SUFU gene fusions.ConclusionsThis study significantly broadens the spectrum of mesothelial tumors associated with fusions, offering insight into novel epithelioid (mesothelial) proliferations with distinctive histological appearances, molecular profiles, and prognoses to guide adapted treatments for patients.
| S-EPMC11326890 | biostudies-literature