Elevated Circulating Activin A Levels in Patients With Malignant Pleural Mesothelioma Are Related to Cancer Cachexia and Reduced Response to Platinum-based Chemotherapy

Our plain-English summary of Elevated Circulating Activin A Levels in Patients With Malignant Pleural Mesothelioma Are Related to Cancer Cachexia and Reduced Response to Platinum-based Chemotherapy, by J. Paajanen, I. Ilonen, H. Lauri, et al (Clinical Lung Cancer, 2020).

The study

• Authors: J. Paajanen, I. Ilonen, H. Lauri, T. Järvinen, E. Sutinen, H. Ollila, E. Rouvinen, K. Lemström, J. Räsänen, O. Ritvos, K. Koli, M. Myllärniemi
• Journal: Clinical Lung Cancer
• Published: 2020;21(3):e142-e150
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Previous preclinical studies have shown that activin A is overexpressed in malignant pleural mesothelioma (MPM), associates with cancer cachexia, and is observed in in vitro resistance to platinum-based chemotherapy. We evaluated circulating activin levels and their endogenous antagonists' follistatin/follistatin-like 3 in intrathoracic tumors.

Materials And Methods: Patients suspected of thoracic malignancy were recruited prior to surgery. Serum samples were collected from 21 patients with MPM, 59 patients with non-small-cell lung cancer (NSCLC), and 22 patients with benign lung lesions. Circulating activin/follistatin levels were measured using enzyme-linked immunosorbent assay and compared with clinicopathologic parameters.

Results: Circulating activin A levels were elevated in patients with MPM when compared with patients with NSCLC or benign lung lesion samples (P < .0001). Also, follistatin and follistatin-like 3 levels were the highest in MPM, although with less difference compared with activin A. Receiver operating characteristic analysis for activin A for separating NSCLC from benign lung lesion showed an area under the curve of 0.856 (95% confidence interval, 0.77-0.94). Activin A levels were higher in patients with cachexia (P < .001). In patients with MPM, activin A levels correlated positively with computed tomography-based baseline tumor size (R = 0.549; P = .010) and the change in tumor size after chemotherapy (R = 0.743; P = .0006). Patients with partial response or stable disease had lower circulating activin A levels than the ones with progressive disease (P = .028).

Conclusion: Activin A serum level could be used as a biomarker in differentiating malignant and benign lung tumors. Circulating activin A levels were elevated in MPM and associates with cancer cachexia and reduced chemotherapy response.

Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

In plain English

This Finnish study measured four blood proteins (activin A, activin B, follistatin and follistatin-like 3) in patients about to have surgery for a suspected chest tumor in the Helsinki region between June 2016 and January 2018. Of 106 patients included, 21 had malignant pleural mesothelioma, 59 had non-small-cell lung cancer, 22 had benign lung lesions and 4 had benign pleuritis. The article does not report asbestos exposure. Activin A was higher in the mesothelioma patients than in the lung cancer and benign lung lesion groups, though the 4 benign pleuritis patients also had raised levels. For telling non-small-cell lung cancer apart from benign lung lesions, activin A had an area under the curve of 0.856 (95% confidence interval 0.77 to 0.94). Activin A was higher in patients with cachexia, a wasting syndrome (median 1.179 versus 0.634 ng/ml). In mesothelioma patients, activin A correlated with tumor size before treatment (R = 0.549). In 12 patients scanned after platinum-based chemotherapy, it correlated with the change in tumor size (R = 0.743). The authors concluded that activin A was associated with cachexia and reduced chemotherapy response in mesothelioma. They noted that clinical data were collected retrospectively and that numerous confounding factors exist.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Biomarker study using blood samples from prospectively recruited patients (biobank samples), with clinical data collected retrospectively from medical records
• Who was studied: Patients with a suspected intrathoracic tumor who gave a serum sample before surgery, recruited from June 2016 to January 2018 in the Helsinki University Hospital region, Finland. Of 149 screened, 106 were included: 21 with malignant pleural mesothelioma (MPM), 59 with non-small-cell lung cancer (NSCLC), 22 with benign lung lesions and 4 with non-specific benign pleuritis.
• Exposure: Not an asbestos exposure study. The factors studied were serum levels of activin A, activin B, follistatin and follistatin-like 3 (FSTL3), measured by ELISA before surgery. These were compared with diagnosis, cachexia, tumor size and response to platinum-based chemotherapy.
• Main results:
  • MPM patients had the highest levels of all the measured proteins compared with NSCLC or benign lung lesion patients.
  • For distinguishing NSCLC patients from benign lung lesion patients, activin A had an area under the curve of 0.856 (95% CI 0.77 to 0.94; P less than 0.001).
  • At a cut-off of 0.488 ng/ml, activin A had a sensitivity of 76% and a specificity of 73% for distinguishing NSCLC from benign lung lesions.
  • Cachexia was more common in MPM patients (12, 57%) than in NSCLC patients (7, 12%) (P less than 0.001).
  • Across patients, activin A was higher in those with cachexia (median 1.179 ng/ml versus 0.634 ng/ml; P less than 0.001).
  • The association between activin A and cachexia remained significant after adjusting for age, gender and CRP (P = 0.047).
  • In MPM patients, activin A correlated with pre-treatment tumor size on CT (R = 0.549; P = 0.010) but not with clinical TNM stage.
  • In MPM patients, activin A did not correlate with CT-based skeletal muscle index.
  • In 12 MPM patients with post-chemotherapy CT scans, activin A correlated with the change in tumor size between the pre- and post-chemotherapy scans (R = 0.743; P = 0.0006). The correlation remained significant after adjustment (P = 0.008).
  • Among these MPM patients, those with partial response or stable tumor size had lower activin A than those with progressive disease (median 1.206 ng/ml versus 3.086 ng/ml; P = 0.028).
  • Benign pleuritis (4 patients) also markedly increased all measured proteins.
• The authors' conclusion: The authors concluded that activin A is elevated in MPM and, to a lesser extent, in NSCLC compared with benign lung lesions. They concluded it could be used as a biomarker to differentiate malignant from benign lung tumors, although numerous confounding factors exist, and that it was associated with cancer cachexia and reduced chemotherapy response in MPM patients.
• Limitations the authors state:
  • Clinical data were collected retrospectively, which may have increased bias.
  • Patients came from thoracic surgery lists, so there were few benign pleuritis and metastatic NSCLC patients. This prevented reliable study of diagnostic accuracy in MPM.
  • The study was not powered to assess the prognostic implications of the biomarkers in MPM.
  • Numerous confounding factors that raise activin A (such as inflammation and age) would reduce its usefulness for diagnosis.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Cachexia, Chemotherapy, Intrathoracic, Lung Cancer, confidence interval, Biomarker.

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• Platinum-DNA damage in leukocyte DNA of patients receiving carboplatin and cisplatin chemotherapy, measured by atomic absorption spectrometry — R.J. Parker, I. Gill, et al. (1991)
• ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma — S. Ting, F.D. Mairinger, et al. (2013)
• Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy — S. Papa, S. Popat, et al. (2013)
• DNA repair polymorphisms and treatment outcomes of patients with malignant mesothelioma treated with gemcitabine-platinum combination chemotherapy — N. Erčulj, V. Kovač, et al. (2012)
• Soluble mesothelin-related peptide level elevation in mesothelioma serum and pleural effusions — H.I. Pass, A. Wali, et al. (2008)

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