Treatment Response Monitoring in Patients with Advanced Malignancies Using Cell-Free SHOX2 and SEPT9 DNA Methylation in Blood: An Observational Prospective Study

Our plain-English summary of Treatment Response Monitoring in Patients with Advanced Malignancies Using Cell-Free SHOX2 and SEPT9 DNA Methylation in Blood: An Observational Prospective Study, by L. de Vos, M. Jung, R.M. Koerber, et al (The Journal of Molecular Diagnostics, 2020).

The study

• Authors: L. de Vos, M. Jung, R.M. Koerber, E.G. Bawden, T.A.W. Holderried, J. Dietrich, F. Bootz, P. Brossart, G. Kristiansen, D. Dietrich
• Journal: The Journal of Molecular Diagnostics
• Published: 2020;22(7):920-933
• Cited by: 26 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Patients with incurable cancer usually receive palliative treatment with significant toxicity and limited efficacy. Methylation analysis of circulating cell-free DNA (ccfDNA) in blood from cancer patients represents a promising approach for minimally invasive, real-time monitoring of treatment response. Short stature homeobox 2 (SHOX2) and septin 9 (SEPT9) methylation was analyzed in N = 8865 malignant and N = 746 normal adjacent tissues across 33 different malignancies from The Cancer Genome Atlas. Furthermore, we performed quantitative SHOX2 and SEPT9 ccfDNA methylation analysis in plasma obtained before and consecutively during treatment from prospectively enrolled N = 115 patients with various advanced cancers. SHOX2 and/or SEPT9 hypermethylation in malignant tissues is present in various carcinomas, sarcoma, melanoma, brain tumors, mesothelioma, and hematopoietic malignancies. Among the prospectively enrolled cancer patients, 61% (70/115) of patients had a baseline-positive blood cumulative ccfDNA methylation score (CMS) and were eligible for response monitoring. Dynamic changes of CMS during treatment were strongly associated with treatment response. A CMS increase indicated response up to 80 days before conventional monitoring. SHOX2 and SEPT9 ccfDNA methylation represents a pan-cancer biomarker and has the potential to be a powerful tool for monitoring treatment response in patients with solid tumors and lymphomas. The early identification of nonresponders might allow for a timely change of treatment regimen.

Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

In plain English

This prospective observational study from University Hospital Bonn, Germany, tested whether two DNA methylation markers measured in blood, SHOX2 and SEPT9, could track how advanced cancers respond to treatment. It did not study asbestos exposure. The authors first analyzed public tissue data from The Cancer Genome Atlas: 8,865 tumor and 746 normal adjacent tissue samples across 33 cancer types, including mesothelioma. In mesothelioma tissue, the area under the curve was 0.80 [0.73-0.87] for SHOX2 and 0.50 [0.44-0.56] for SEPT9. This figure measures how well a marker separates tumor from normal tissue. SEPT9 in mesothelioma was among the few exceptions where tumor methylation did not differ significantly from normal tissue. The authors then tested blood from 115 patients with various advanced cancers, none listed as having mesothelioma. Of these, 61% (70/115) had a positive baseline combined score. Among 20 patients followed during treatment, the score fell under systemic therapy in all 20. Score changes appeared up to 80 days before scans showed progression. Three patients had a negative score when their disease progressed. The authors concluded the markers are promising for monitoring treatment response.

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: Prospective observational study of blood samples, combined with an analysis of publicly available tumor tissue methylation data from The Cancer Genome Atlas (TCGA)
• Who was studied: Tissue: 8,865 tumor and 746 normal adjacent tissue samples from 33 cancer types in TCGA, including mesothelioma (MESO). Blood: 115 patients with various advanced cancers treated at the University Hospital of Bonn between 2013 and 2017: 77 carcinomas, 9 sarcomas, 2 germ cell tumors, 2 neuroendocrine tumors and 25 lymphomas. No mesothelioma patients were listed in the blood cohort. Repeated blood samples were taken from 30 patients. After excluding 9 who were negative at baseline and 1 without clinical information, 20 were analyzed for monitoring.
• Exposure: No asbestos or other fiber exposure was studied. The study measured SHOX2 and SEPT9 DNA methylation in tumor tissue and in circulating cell-free DNA in plasma. In blood, the two markers were combined into a cumulative methylation score (CMS), with a positive cut-off of 0.16%. Blood was sampled before and during chemotherapy, targeted therapy, immunotherapy and radiotherapy.
• Main results:
  • In TCGA tissue, methylation differed significantly between tumors and normal adjacent tissue, with a few exceptions. For SEPT9 the exceptions included mesothelioma (MESO); for SHOX2 they were OV, KIRC, KIRP and THCA.
  • In TCGA mesothelioma tissue, the area under the curve was 0.80 [0.73-0.87] for SHOX2 and 0.50 [0.44-0.56] for SEPT9.
  • In the blood cohort, 61% (70/115) of patients had a positive baseline cumulative methylation score.
  • In all 20 monitored patients, the score decreased under systemic therapy.
  • Repeatedly low methylation correlated with regressive or stable disease on CT in 85% (17/20) of monitored patients.
  • Among patients whose score rose, progression was seen on imaging before the rise in 2 cases, at the same time in 2 cases, and after the rise in 5 cases. Changes in the score were detectable up to 80 days before CT diagnosis of progression.
  • In 3 of the 20 monitored patients (two pancreatic adenocarcinomas, one lung adenocarcinoma), the score was negative when disease progression was present.
• The authors' conclusion: The authors concluded that elevated SHOX2 and SEPT9 methylation in cell-free DNA occurs across many cancer types and correlates with clinical disease burden. They called it a promising biomarker for treatment response monitoring in advanced solid tumors and lymphomas.
• Limitations the authors state:
  • Only a few blood samples were available for several cancer types, so the authors said no general statement can be made for those groups.
  • For several patients, the intervals between blood samples were long. In those cases the authors could not tell whether blood methylation signalled progression earlier than conventional monitoring.
  • Score changes did not correlate with progression in 15% (3/20) of baseline-positive patients. In one of them, who developed brain metastases, the authors suggested the tumor DNA might not have crossed the blood-brain barrier.

Topics

Medical terms in this study, explained in our Lexicon: Palliative Care, Carcinoma, Sarcoma, Mesothelioma, Biomarker.

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