bims-mesote Biomed News
on Mesothelioma
Issue of 2021‒06‒13
four papers selected by
Laura Mannarino
Humanitas Research

  1. J Thorac Oncol. 2021 Jun 08. pii: S1556-0864(21)02189-4. [Epub ahead of print]
      INTRODUCTION: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan® proteomics and Fibulin-3 appeared highly accurate, but SOMAscan® has not been validated prospectively and subsequent Fibulin-3 data have been contradictory.METHODS: A multi-centre prospective observational study was performed in 22 centres, generating a large intention-to-diagnose cohort. Blood sampling, processing and diagnostic assessment were standardised, including 1-year follow-up. Plasma Fibulin-3 was measured using two enzyme-linked immunosorbent assays (ELISAs: CloudClone (used in previous studies) and BosterBio). Serum proteomics were measured using the SOMAscan® assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve (AUC)) was benchmarked against serum Mesothelin (Mesomark®). Biomarkers were correlated against primary tumour volume, inflammatory markers and asbestos exposure.
    RESULTS: 638 patients with suspected pleural malignancy (SPM) and 110 asbestos exposed controls (AECs) were recruited. SOMAscan® reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in differentiating non-MPM SPM patients. Fibulin-3 (by BosterBio following failed CloudClone validation) demonstrated 7.4% and 11.9% sensitivity at 95% specificity in MPM v. non-MPM SPM and AECs respectively (associated AUCs 0.611 (0.557-0.664), p=0.0015) and 0.516 (0.443-0.589), p=0.671), both inferior to Mesothelin. SOMAscan® proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumour volume.
    CONCLUSIONS: SOMAscan® may prove useful as a future screening test for MPM in asbestos exposed persons. Neither Fibulin-3 nor SOMAscan® should be used for diagnosis or pathway stratification.
    Keywords:  Biomarker; Fibulin-3; Mesothelin; Mesothelioma; SOMAscan
  2. Drugs. 2021 Jun 09.
      Immune checkpoint inhibitors (ICI) have shown important but variable efficacy in mesothelioma despite a lack of strong biological rationale. Initial trials assessed ICI monotherapy in patients with relapsed mesothelioma, with objective response rates (ORR) between 4.5 and 29%, median progression-free survival (PFS) between 2.5-6.2 months, and median overall survival (OS) between 7.7 and 18.0 months. In randomised trials of chemotherapy pre-treated patients, nivolumab was recently shown to improve PFS compared to placebo, but tremelimumab was not superior to placebo, and there was no difference in OS between pembrolizumab and chemotherapy. However, response to combination ICI appear more promising in both pre-treated and treatment-naïve mesothelioma. The randomised Phase 3 trial of upfront ipilimumab-nivolumab versus platinum-pemetrexed chemotherapy demonstrated improved OS favouring ipilimumab-nivolumab (HR 0.74, 96.6% CI 0.60-0.91; p = 0.0020), establishing this regimen as a new standard of care, especially in non-epithelioid histological subtypes. However, initially PFS was poorer in the ipilimumab-nivolumab than chemotherapy treatment arms. A single-arm Phase 2 trial of upfront platinum chemotherapy and durvalumab met its primary endpoint, with a 6-month PFS of 57% (95% CI 44-70) with chemo-immunotherapy under evaluation as an alternative upfront regimen. Several questions remain unanswered. Comparative studies of chemo-immunotherapy versus chemotherapy are underway, but these do not compare chemo-immunotherapy to combination ICI. There is a critical need to establish predictive biomarkers to improve patient selection. As ICI use moves into the front-line setting, patient selection, role for operable patients, and understanding ICI resistance mechanisms alongside role of ICI rechallenge in previous responders need further evaluation.
  3. Ann Surg. 2021 Jun 04.
      BACKGROUND: The outcomes associated with receipt of adjuvant radiation in patients following surgery for malignant pleural mesothelioma (MPM) are poorly understood.OBJECTIVE: The objective of this study was to use two registries to compare the outcomes of patients receiving adjuvant radiation or no radiation following definitive surgery for pathologic stage I-III MPM.
    METHODS: Patients with resected pathologic stage I-III MPM were identified from the Duke University registry (1996-2016) and National Cancer Database (2004-2015). The primary outcome was overall survival (OS). Propensity score-matched and landmark subgroup analyses were performed. A total of 212 institutional and 1615 NCDB patients met criteria. In both cohorts, patients who underwent radiation were more likely to have margin-negative resection and more advanced pathologic stage. At a landmark time of 4.4 and 4.7 months from surgery, Duke (HR 1.14; 95%CI 0.62-2.11) and NCDB patients (HR 0.97; 95%CI 0.81-1.17) who received adjuvant radiation did not experience improved survival compared to those who did not receive radiation in multivariable analysis. Duke patients who received radiation had similar incidence of recurrence and time to both overall recurrence and ipsilateral recurrence (HR 0.87; 95%CI 0.43-1.77) compared to those who did not. Duke patients experienced 100 grade 1/2, 21 grade 3/4, and one grade 5 toxicity events during radiation.
    CONCLUSION: In this dual registry analysis of patients with resected stage I-III MPM, the receipt of adjuvant hemithoracic radiation was not associated with improved survival compared to no radiation.
  4. Cancer Sci. 2021 Jun 11.
      Malignant mesothelioma (MM) is one of the most aggressive tumors. We conducted bioinformatics analysis using Cancer Cell Line Encyclopedia (CCLE) datasets to identify new molecular markers in MM. Overexpression of oxytocin receptor (OXTR), which is a G-protein-coupled receptor for the hormone and neurotransmitter oxytocin, mRNA was distinctively identified in MM cell lines. Therefore, we assessed the role of OXTR and its clinical relevance in MM. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and OXTR mRNA expression using The Cancer Genome Atlas (TCGA) datasets. The function of OXTR and the efficacy of its antagonists were investigated in vitro and in vivo using MM cell lines. Consistent with the findings from CCLE datasets analysis, OXTR mRNA expression was highly increased in MM tissues compared with other cancer types in the TCGA datasets, and MM cases with high OXTR expression showed poor overall survival. Moreover, OXTR knockdown dramatically decreased MM cell proliferation in cells with high OXTR expression via tumor cell cycle disturbance, whereas oxytocin treatment significantly increased MM cell growth. OXTR antagonists, which have high selectivity for OXTR, inhibited the growth of MM cell lines with high OXTR expression, and oral administration of the OXTR antagonist, cligosiban, significantly suppressed MM tumor progression in a xenograft model. Our findings suggest that OXTR plays a crucial role in MM cell proliferation and is a promising therapeutic target that may broaden potential therapeutic options and could be a prognostic biomarker of MM.
    Keywords:  G-protein coupled receptors; G1 phase cell cycle checkpoints; malignant mesothelioma; oxytocin receptor; oxytocin receptor antagonists