Individualized Cell-Free DNA Monitoring With Chromosomal Junctions for Mesothelioma

Our plain-English summary of Individualized Cell-Free DNA Monitoring With Chromosomal Junctions for Mesothelioma, by K. Parikh, F.R. Harris, G. Karagouga, et al (JTO Clinical and Research Reports, 2024).

The study

• Authors: K. Parikh, F.R. Harris, G. Karagouga, A. Schrandt, J. Mandrekar, S. Johnson, A. McCune, D. Sadeghian, D. Roy, K. Polonis, A. Gaitatzes, A.O. Bungum, E.S. Edell, M.J. Borad, T. Peikert, F. Kosari, J. Cheville, G. Vasmatzis, A.S. Mansfield
• Journal: JTO Clinical and Research Reports
• Published: 2024;5(12):100692
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: The spatially complex nature of mesothelioma and interventions like pleurodesis, surgery, and radiation often complicate imaging-based assessment. Further, cell-free DNA (cfDNA) based monitoring strategies are inadequate for mesothelioma, given the presence of a few recurring nonsynonymous somatic variants. However, patient-specific chromosomal rearrangements are commonly found in mesothelioma. Our study objective was to develop an individualized cfDNA assay to enable blood-based monitoring using circulating tumor DNA (ctDNA) in mesothelioma. We hypothesized that the unique chromosomal rearrangement junctions found in mesothelioma could be employed for individualized ctDNA detection and disease monitoring.

Methods: DNA was extracted from tumor specimens for whole genome sequencing. Chromosomal junctions, prioritized by highest allele frequency and low homology to the rest of the genome, were selected for detection. Primers and Taqman probes were designed to span the junctions, forming personalized junction panels. Patient plasma obtained before therapy and at response assessment was tested for the presence of personalized junctions via quantitative polymerase chain reaction.

Results: Our study included nine patients, four with peritoneal and five with pleural mesothelioma. 763 chromosomal junctions were identified in the tumors of all cases. We selected three to five junctions per sample for quantitative polymerase chain reaction. We detected 25/30 (83%) of selected junctions in the plasma of seven out of nine patients (78%). Cell-free junction detection at follow-up was concordant with disease status: cfDNA junctions were detected in three patients with persistent disease, and not detected in a patient with no evidence of disease after surgery.

Conclusions: With further validation, individualized ctDNA junction assays could supplement imaging for disease monitoring in mesothelioma.

© 2024 The Authors.

In plain English

This pilot study tested whether a personalized blood test could track mesothelioma. It did not examine asbestos exposure. The authors studied nine patients at Mayo Clinic, five with pleural and four with peritoneal mesothelioma. For each patient, the authors sequenced the tumor's whole genome. They found the points where pieces of chromosomes had broken and rejoined, called junctions, and designed tests to look for those junctions in tumor DNA circulating in the blood. They found 763 junctions in the nine tumors and tested 30 selected junctions in blood. Before treatment, tumor DNA was detected in the blood of seven of nine patients (78%), with 25 of the 30 junctions (83%) detected. Four patients gave later blood samples. Junctions stayed detectable in three patients with persistent disease. They were not detected in one patient who had no visible disease on imaging after treatment and surgery. The authors concluded that the approach showed proof-of-concept but needs improvement and validation in larger studies. They noted the small sample and short follow-up.

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: Pilot study developing and testing an individualized blood (cell-free DNA) assay; seven patients enrolled prospectively and two drawn retrospectively from a tissue biorepository
• Who was studied: 9 patients with biopsy-proven mesothelioma at Mayo Clinic, Rochester, Minnesota (5 pleural, 4 peritoneal). Five were men and four were women, with a median age of 66 years (range 47 to 76). Histology was epithelioid in 5, biphasic in 3 and sarcomatoid in 1. Prospective enrollment ran from September 2020 to September 2021.
• Exposure: Not studied. The article does not assess asbestos or any other exposure; it tests a blood-based tumor DNA assay.
• Main results:
  • Whole genome sequencing of the nine tumor specimens found 763 chromosomal junctions in total (median 79 per tumor, range 22 to 199).
  • At baseline, tumor DNA was detected in the blood plasma of 7 of 9 patients (78%), and 25 of the 30 junctions tested in plasma (83%) were detected.
  • Of the four patients with follow-up blood samples, three had detectable junctions at follow-up, and the authors report this corresponded with persistent disease.
  • In one patient with epithelioid peritoneal mesothelioma (MesoMon001), no junctions were detected after preoperative therapy and surgery. At last follow-up this patient had no visible disease on imaging.
  • In one patient (MesoMon003) treated with pembrolizumab, junction detection decreased at first follow-up alongside a favorable response. It increased at second follow-up, and the authors report that disease progression was then confirmed on CT imaging.
  • Junctions were not detected in the plasma of 2 of 9 patients, even though junctions were found in all tumor specimens.
• The authors' conclusion: The authors concluded that their pilot study provides proof-of-concept of a blood-based, personalized serial monitoring tool for mesothelioma. They added that further improvement in junction selection and specimen handling, and validation in larger studies, could potentially provide a minimally invasive monitoring tool, especially where imaging is difficult to interpret.
• Limitations the authors state:
  • Small sample size, which the authors attribute to the rarity of mesothelioma and the COVID-19 pandemic
  • Three enrolled patients did not return for later blood samples during the pandemic and were treated locally
  • Short follow-up time, with only limited on-treatment specimens
  • Tumor DNA was not detected in two patients. The authors say this could be due to lack of tumor DNA shedding into the blood, their probe design, blood processing, or other uncharacterized biological factors.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleurodesis, ctDNA, Pleural Mesothelioma.

Related studies

• Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma — A.S. Mansfield, T. Peikert, et al. (2019)
• Treatment Response Monitoring in Patients with Advanced Malignancies Using Cell-Free SHOX2 and SEPT9 DNA Methylation in Blood: An Observational Prospective Study — L. de Vos, M. Jung, et al. (2020)
• Dynamics and survival associations of T cell receptor clusters in patients with pleural mesothelioma treated with immunotherapy — A.P. Desai, F. Kosari, et al. (2023)
• Chromosomal rearrangements and their neoantigenic potential in mesothelioma — A.S. Mansfield, T. Peikert, et al. (2020)
• Variation in drug sensitivity of malignant mesothelioma cell lines with substantial effects of selenite and bortezomib, highlights need for individualized therapy — A. Szulkin, G. Nilsonne, et al. (2013)
• Asbestos-associated chromosomal changes in human mesothelial cells — J.F. Lechner, T. Tokiwa, et al. (1985)

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