Circulating cell-free DNA-based biomarkers for prognostication and disease monitoring in adrenocortical carcinoma

Juliane Lippert; Gabrielle Smith; Silke Appenzeller; Laura-Sophie Landwehr; Alessandro Prete; Sonja Steinhauer; Miriam Asia; Hanna Urlaub; Yasir Elhassan; Stefan Kircher; Wiebke Arlt; Martin Fassnacht; Barbara Altieri; Cristina Ronchi

doi:10.1093/ejendo/lvae022

Circulating cell-free DNA-based biomarkers for prognostication and disease monitoring in adrenocortical carcinoma

Juliane Lippert, Gabrielle Smith, Silke Appenzeller, Laura-Sophie Landwehr, Alessandro Prete, Sonja Steinhauer, Miriam Asia, Hanna Urlaub, Yasir Elhassan, Stefan Kircher, Wiebke Arlt, Martin Fassnacht, Barbara Altieri, Cristina Ronchi^*

^*Corresponding author for this work

Metabolism and Systems Research

Research output: Contribution to journal › Article › peer-review

Abstract

Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. The aim of the study was to investigate the role of circulating cell-free DNA (ccfDNA)-related biomarkers (BM) for prognostication and monitoring of ACC.

We investigated 34 patients with ACC and 23 healthy subjects (HS) as controls. ccfDNA was extracted by commercial kits and ccfDNA concentrations quantified by fluorimeter (BM1). Targeted sequencing was performed using a customised panel of 27 ACC-specific genes. Leucocyte DNA was used to discriminate somatic variants (BM2), while tumour DNA was sequenced in 22/34 cases for comparison. Serial ccfDNA samples were collected during follow-up in 19 ACC patients (median period 9 months) and analysed in relationship with standard radiological imaging.

ccfDNA concentrations were higher in ACC than HS (mean±SD, 1.15±1.56 vs 0.05±0.05 ng/µl, P<0.0001), 96% of them being above the cut-off of 0.146 ng/µl (mean HS+2SD, positive BM1). At ccfDNA sequencing, 47% of ACC showed at least one somatic mutation (positive BM2). A combined ccfDNA-BM score was strongly associated with both progression-free and overall survival (HR=2.63, 95%CI=1.13-6.13, P=0.010, and HR=5.98, 95%CI=2.29-15.6, P=0.0001, respectively). During disease monitoring, positive BM2 showed the best specificity (100%) and sensitivity (67%) to detect ACC recurrence or progress compared to BM1.

In conclusion, ccfDNA-related BMs are frequently detected in ACC patients and represent a promising, minimally invasive tool to predict clinical outcome and complement surveillance imaging. Our findings will be validated in a larger cohort of ACCs with long-term follow-up.

Original language	English
Article number	lvae022
Journal	European Journal of Endocrinology
Early online date	7 Mar 2024
DOIs	https://doi.org/10.1093/ejendo/lvae022
Publication status	E-pub ahead of print - 7 Mar 2024

Bibliographical note

Financial support:
This work has been supported by the Deutsche Krebshilfe (70113526 M.F., C.L.R, and S.A.), the AMEND (ACC Research Award 2019 and 2021 to C.L.R.), and the European Reference Network on Rare Endocrine Conditions (Endo-ERN). A.P. receives support from the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (grant reference number NIHR203326), while C.L.R receives support from HRA Pharma Rare Disease (research grant). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care UK.

Keywords

ccfDNA
adrenal cancer
personalised medicine

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10.1093/ejendo/lvae022Licence: Creative Commons: Attribution-NonCommercial (CC BY-NC)

LippertJ2024CirculatingAccepted author manuscript, 1.4 MBLicence: Creative Commons: Attribution-NonCommercial (CC BY-NC)

Cite this

Lippert, J., Smith, G., Appenzeller, S., Landwehr, L.-S., Prete, A., Steinhauer, S., Asia, M., Urlaub, H., Elhassan, Y., Kircher, S., Arlt, W., Fassnacht, M., Altieri, B., & Ronchi, C. (2024). Circulating cell-free DNA-based biomarkers for prognostication and disease monitoring in adrenocortical carcinoma. European Journal of Endocrinology, Article lvae022. Advance online publication. https://doi.org/10.1093/ejendo/lvae022

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title = "Circulating cell-free DNA-based biomarkers for prognostication and disease monitoring in adrenocortical carcinoma",

abstract = "Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. The aim of the study was to investigate the role of circulating cell-free DNA (ccfDNA)-related biomarkers (BM) for prognostication and monitoring of ACC.We investigated 34 patients with ACC and 23 healthy subjects (HS) as controls. ccfDNA was extracted by commercial kits and ccfDNA concentrations quantified by fluorimeter (BM1). Targeted sequencing was performed using a customised panel of 27 ACC-specific genes. Leucocyte DNA was used to discriminate somatic variants (BM2), while tumour DNA was sequenced in 22/34 cases for comparison. Serial ccfDNA samples were collected during follow-up in 19 ACC patients (median period 9 months) and analysed in relationship with standard radiological imaging.ccfDNA concentrations were higher in ACC than HS (mean±SD, 1.15±1.56 vs 0.05±0.05 ng/µl, P<0.0001), 96% of them being above the cut-off of 0.146 ng/µl (mean HS+2SD, positive BM1). At ccfDNA sequencing, 47% of ACC showed at least one somatic mutation (positive BM2). A combined ccfDNA-BM score was strongly associated with both progression-free and overall survival (HR=2.63, 95%CI=1.13-6.13, P=0.010, and HR=5.98, 95%CI=2.29-15.6, P=0.0001, respectively). During disease monitoring, positive BM2 showed the best specificity (100%) and sensitivity (67%) to detect ACC recurrence or progress compared to BM1.In conclusion, ccfDNA-related BMs are frequently detected in ACC patients and represent a promising, minimally invasive tool to predict clinical outcome and complement surveillance imaging. Our findings will be validated in a larger cohort of ACCs with long-term follow-up.",

keywords = "ccfDNA, adrenal cancer, personalised medicine",

author = "Juliane Lippert and Gabrielle Smith and Silke Appenzeller and Laura-Sophie Landwehr and Alessandro Prete and Sonja Steinhauer and Miriam Asia and Hanna Urlaub and Yasir Elhassan and Stefan Kircher and Wiebke Arlt and Martin Fassnacht and Barbara Altieri and Cristina Ronchi",

note = "Financial support: This work has been supported by the Deutsche Krebshilfe (70113526 M.F., C.L.R, and S.A.), the AMEND (ACC Research Award 2019 and 2021 to C.L.R.), and the European Reference Network on Rare Endocrine Conditions (Endo-ERN). A.P. receives support from the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (grant reference number NIHR203326), while C.L.R receives support from HRA Pharma Rare Disease (research grant). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care UK.",

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T1 - Circulating cell-free DNA-based biomarkers for prognostication and disease monitoring in adrenocortical carcinoma

AU - Lippert, Juliane

AU - Smith, Gabrielle

AU - Appenzeller, Silke

AU - Landwehr, Laura-Sophie

AU - Prete, Alessandro

AU - Steinhauer, Sonja

AU - Asia, Miriam

AU - Urlaub, Hanna

AU - Elhassan, Yasir

AU - Kircher, Stefan

AU - Arlt, Wiebke

AU - Fassnacht, Martin

AU - Altieri, Barbara

AU - Ronchi, Cristina

N1 - Financial support: This work has been supported by the Deutsche Krebshilfe (70113526 M.F., C.L.R, and S.A.), the AMEND (ACC Research Award 2019 and 2021 to C.L.R.), and the European Reference Network on Rare Endocrine Conditions (Endo-ERN). A.P. receives support from the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (grant reference number NIHR203326), while C.L.R receives support from HRA Pharma Rare Disease (research grant). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care UK.

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Y1 - 2024/3/7

N2 - Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. The aim of the study was to investigate the role of circulating cell-free DNA (ccfDNA)-related biomarkers (BM) for prognostication and monitoring of ACC.We investigated 34 patients with ACC and 23 healthy subjects (HS) as controls. ccfDNA was extracted by commercial kits and ccfDNA concentrations quantified by fluorimeter (BM1). Targeted sequencing was performed using a customised panel of 27 ACC-specific genes. Leucocyte DNA was used to discriminate somatic variants (BM2), while tumour DNA was sequenced in 22/34 cases for comparison. Serial ccfDNA samples were collected during follow-up in 19 ACC patients (median period 9 months) and analysed in relationship with standard radiological imaging.ccfDNA concentrations were higher in ACC than HS (mean±SD, 1.15±1.56 vs 0.05±0.05 ng/µl, P<0.0001), 96% of them being above the cut-off of 0.146 ng/µl (mean HS+2SD, positive BM1). At ccfDNA sequencing, 47% of ACC showed at least one somatic mutation (positive BM2). A combined ccfDNA-BM score was strongly associated with both progression-free and overall survival (HR=2.63, 95%CI=1.13-6.13, P=0.010, and HR=5.98, 95%CI=2.29-15.6, P=0.0001, respectively). During disease monitoring, positive BM2 showed the best specificity (100%) and sensitivity (67%) to detect ACC recurrence or progress compared to BM1.In conclusion, ccfDNA-related BMs are frequently detected in ACC patients and represent a promising, minimally invasive tool to predict clinical outcome and complement surveillance imaging. Our findings will be validated in a larger cohort of ACCs with long-term follow-up.

AB - Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. The aim of the study was to investigate the role of circulating cell-free DNA (ccfDNA)-related biomarkers (BM) for prognostication and monitoring of ACC.We investigated 34 patients with ACC and 23 healthy subjects (HS) as controls. ccfDNA was extracted by commercial kits and ccfDNA concentrations quantified by fluorimeter (BM1). Targeted sequencing was performed using a customised panel of 27 ACC-specific genes. Leucocyte DNA was used to discriminate somatic variants (BM2), while tumour DNA was sequenced in 22/34 cases for comparison. Serial ccfDNA samples were collected during follow-up in 19 ACC patients (median period 9 months) and analysed in relationship with standard radiological imaging.ccfDNA concentrations were higher in ACC than HS (mean±SD, 1.15±1.56 vs 0.05±0.05 ng/µl, P<0.0001), 96% of them being above the cut-off of 0.146 ng/µl (mean HS+2SD, positive BM1). At ccfDNA sequencing, 47% of ACC showed at least one somatic mutation (positive BM2). A combined ccfDNA-BM score was strongly associated with both progression-free and overall survival (HR=2.63, 95%CI=1.13-6.13, P=0.010, and HR=5.98, 95%CI=2.29-15.6, P=0.0001, respectively). During disease monitoring, positive BM2 showed the best specificity (100%) and sensitivity (67%) to detect ACC recurrence or progress compared to BM1.In conclusion, ccfDNA-related BMs are frequently detected in ACC patients and represent a promising, minimally invasive tool to predict clinical outcome and complement surveillance imaging. Our findings will be validated in a larger cohort of ACCs with long-term follow-up.

KW - ccfDNA

KW - adrenal cancer

KW - personalised medicine

U2 - 10.1093/ejendo/lvae022

DO - 10.1093/ejendo/lvae022

M3 - Article

SN - 0804-4643

JO - European Journal of Endocrinology

JF - European Journal of Endocrinology

M1 - lvae022

ER -

Circulating cell-free DNA-based biomarkers for prognostication and disease monitoring in adrenocortical carcinoma

Abstract

Bibliographical note

Keywords

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Cite this