Soluble High Mobility Group Box 1 (HMGB1) Is a Promising Biomarker for Prediction of Therapy Response and Prognosis in Advanced Lung Cancer Patients

Our plain-English summary of Soluble High Mobility Group Box 1 (HMGB1) Is a Promising Biomarker for Prediction of Therapy Response and Prognosis in Advanced Lung Cancer Patients, by N.A. Handke, A.B.A. Rupp, N. Trimpop, et al (Diagnostics, 2021).

The study

• Authors: N.A. Handke, A.B.A. Rupp, N. Trimpop, J. von Pawel, S. Holdenrieder
• Journal: Diagnostics
• Published: 2021;11(2)
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: High mobility group box 1 protein (HMGB1) is known for its significant elevation in a multitude of tumors and benign diseases. In this study, we investigated the relevance of soluble HMGB1 for the prediction and monitoring of therapy response as well as the estimation of prognosis in advanced lung cancer.

Materials And Methods: In a retrospective study, HMGB1 levels were assessed by an enzyme-linked immunosorbent assay (ELISA) in the sera of 96 patients with advanced lung cancer (79 non-small-cell lung carcinoma (NSCLC); 14 small cell lung carcinoma (SCLC), 3 Mesothelioma) prior to cycles 1, 2, and 3 of chemotherapy and correlated with radiological therapy response after 2 and 4 cycles as well as with overall survival. In addition, HMGB1 was compared with established tumor markers cytokeratin 19-fragments (CYFRA 21-1), carcinoembryonic antigen (CEA) and neuron specific enolase (NSE).

Results: While pretherapeutic HMGB1 levels were not predictive or prognostically relevant in NSCLC patients, HMGB1 values prior to cycles 2 and 3 as well as kinetics from cycle 1 to 2 discriminated significantly between patients with good (remission and stable disease) and poor response (progression). Performance of HMGB1 in receiver operating characteristic (ROC) analyses of NSCLC patients, with areas under the curve (AUCs) of 0.690 at cycle 2 and 0.794 at cycle 3 as well as sensitivities of 34.4% and 37.5%, respectively, for progression at 90% specificity, was comparable with the best tumor-associated antigen CYFRA 21-1 (AUCs 0.719 and 0.799; sensitivities of 37.5% and 41.7%, respectively). Furthermore, high concentrations of HMGB1 at cycles 2 and 3 were associated with shorter overall survival in NSCLC patients.

Conclusion: Soluble HMGB1 is a promising biomarker for prediction of therapy response and prognosis in advanced NSCLC patients.

In plain English

This retrospective study measured a blood protein, soluble HMGB1, in stored serum from 96 patients with advanced lung cancer who received chemotherapy at the Asklepios-Lungenfachklinik Gauting, Germany, between January 1999 and June 2002. HMGB1 was measured later at University Hospital Bonn. The group included 79 patients with non-small-cell lung carcinoma (NSCLC), 14 with small-cell lung carcinoma (SCLC) and 3 with mesothelioma. The 3 mesothelioma patients were excluded because there were too few. The study did not examine asbestos exposure. Samples were taken before chemotherapy cycles 1, 2 and 3. HMGB1 was compared with the established markers CYFRA 21-1, CEA and NSE. In NSCLC patients, HMGB1 before treatment did not separate responders from those whose cancer progressed. Levels before cycles 2 and 3 were significantly lower in responders. Before cycle 3, NSCLC patients with HMGB1 below 2.69 ng/mL had a median overall survival of 490 days (95% confidence interval 296–684). Those above it had 134 days (95% confidence interval 98–170). In SCLC patients, HMGB1 did not significantly separate response groups. The authors concluded that HMGB1 was a valuable marker in advanced NSCLC. They noted the study was retrospective and lacked an independent validation cohort.

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: retrospective study of stored serum samples (biomarker study)
• Who was studied: 96 patients with newly diagnosed or recurrent advanced lung cancer (79 NSCLC, 14 SCLC, 3 mesothelioma) who received chemotherapy at the Asklepios-Lungenfachklinik Gauting between January 1999 and June 2002. The mesothelioma patients were excluded from analyses because of their small number.
• Exposure: No asbestos or other environmental exposure was studied. The study measured serum HMGB1, together with the markers CEA, CYFRA 21-1 and NSE, before chemotherapy cycles 1, 2 and 3. HMGB1 was measured later at University Hospital Bonn.
• Main results:
  • In NSCLC patients, levels of HMGB1, CEA and CYFRA 21-1 before therapy did not distinguish response groups.
  • In NSCLC patients, HMGB1 and CYFRA 21-1 levels before cycles 2 and 3 were significantly lower in patients who responded than in patients whose disease progressed.
  • For detecting progression in NSCLC, HMGB1 had an AUC of 0.690 (p = 0.010) before cycle 2 and 0.794 (p < 0.001) before cycle 3. CYFRA 21-1 had 0.719 (p = 0.003) and 0.799 (p < 0.001).
  • In NSCLC, at 90% specificity, HMGB1 detected progression with sensitivities of 34.4% (cycle 2) and 37.5% (cycle 3).
  • In NSCLC, HMGB1 below the median cutoff before cycle 2 was linked to longer median overall survival: 239 vs. 184 days (p = 0.038).
  • In NSCLC, before cycle 3, patients with HMGB1 below the cutoff of 2.69 ng/mL had a median overall survival of 490 days (95% CI 296–684). Patients above the cutoff had 134 days (95% CI 98–170). The p-value was less than 0.001.
  • In NSCLC, HMGB1 measured before therapy showed no prognostic value.
  • In SCLC patients, HMGB1 did not distinguish responders from non-responders.
• The authors' conclusion: The authors concluded that soluble HMGB1 was a new and highly valuable biomarker for predicting and monitoring therapy response and prognosis in advanced NSCLC, with results comparable to CYFRA 21-1. They said further studies would need to confirm this.
• Limitations the authors state:
  • Retrospective design
  • Long storage time before HMGB1 measurement, and use of a research-use-only immunoassay
  • No independent validation cohort
  • Small number of SCLC patients

Topics

Medical terms in this study, explained in our Lexicon: High Mobility Group Box 1 (HMGB1), Biomarker, Prognosis, Lung Cancer, Carcinoma, Mesothelioma, Chemotherapy, Overall Survival.

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