Circulating tumour DNA at baseline for individualised prognostication in patients with chemotherapy-naïve metastatic colorectal cancer. An AGEO prospective study

Jean-Baptiste Bachet; Pierre Laurent-Puig; Aurelia Meurisse; Olivier Bouché; Léo Mas; Valérie Taly; Romain Cohen; Jean-Marc Gornet; Pascal Artru; Samy Louafi; Anne Thirot-Bidault; Isabelle Baumgaertner; Romain Coriat; David Tougeron; Thierry Lecomte; Florence Mary; Thomas Aparicio; Lysiane Marthey; Hélène Blons; Dewy Vernerey; Julien Taieb

doi:10.1016/j.ejca.2023.05.022

Circulating tumour DNA at baseline for individualised prognostication in patients with chemotherapy-naïve metastatic colorectal cancer. An AGEO prospective study

Eur J Cancer. 2023 Aug:189:112934. doi: 10.1016/j.ejca.2023.05.022. Epub 2023 Jun 7.

Authors

Jean-Baptiste Bachet¹, Pierre Laurent-Puig², Aurelia Meurisse³, Olivier Bouché⁴, Léo Mas⁵, Valérie Taly⁶, Romain Cohen⁷, Jean-Marc Gornet⁸, Pascal Artru⁹, Samy Louafi¹⁰, Anne Thirot-Bidault¹¹, Isabelle Baumgaertner¹², Romain Coriat¹³, David Tougeron¹⁴, Thierry Lecomte¹⁵, Florence Mary¹⁶, Thomas Aparicio¹⁷, Lysiane Marthey¹⁸, Hélène Blons¹⁹, Dewy Vernerey³, Julien Taieb²⁰

Affiliations

¹ Department of Hepato-gastroenterology, Groupe Hospitalier Pitié Salpêtrière, Paris, France; AGEO (Association des Gastroentérologues Oncologues), Paris, France; Sorbonne Universités, UPMC Université, Paris 06, France; Centre de Recherche des Cordeliers, INSERM, CNRS SNC 5096, Sorbonne Université, Université Paris Cité, Paris, France.
² Centre de Recherche des Cordeliers, INSERM, CNRS SNC 5096, Sorbonne Université, Université Paris Cité, Paris, France; Institut du cancer Paris CARPEM, AP-HP, Hopital européen Georges Pompidou, Paris, France. Electronic address: [email protected].
³ Methodology and Quality of Life Unit in Oncology, University Hospital of Besançon, Besançon, France; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Besançon, France.
⁴ AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Hepato-Gastroenterology, CHU Reims, Reims, France.
⁵ Department of Hepato-gastroenterology, Groupe Hospitalier Pitié Salpêtrière, Paris, France; AGEO (Association des Gastroentérologues Oncologues), Paris, France.
⁶ Centre de Recherche des Cordeliers, INSERM, CNRS SNC 5096, Sorbonne Université, Université Paris Cité, Paris, France.
⁷ AGEO (Association des Gastroentérologues Oncologues), Paris, France; Sorbonne Universités, UPMC Université, Paris 06, France; Department of Oncology, Hôpital Saint-Antoine, Paris, France.
⁸ AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Hôpital Saint-Louis, Paris, France.
⁹ AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Ramsay Hôpital Privé Jean Mermoz, Lyon, France.
¹⁰ AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France; Department of Gastroenterology, Groupe Hospitalier Nord Essonne, Longjumeau, France.
¹¹ AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Hôpital Kremlin Bicêtre, Le Kremlin-Bicêtre, France.
¹² AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Oncology, Hôpital Henri Mondor, Créteil, France.
¹³ AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Hôpital Cochin, Université Paris Cité, Paris, France.
¹⁴ AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology and Hepatology, Centre Hospitalo-universitaire de Poitiers, Poitiers, France.
¹⁵ AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Hepatology and Digestive Oncology, Centre Hospitalo-universitaire de Tours, Tours, France.
¹⁶ AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Hôpital Avicenne, Bobigny, France.
¹⁷ AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Hôpital Saint-Louis, Paris, France; Department of Gastroenterology, Hôpital Antoine Béclère, Clamart, France.
¹⁸ AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Biochemistry, Hôpital Européen Georges Pompidou, Paris, France.
¹⁹ Centre de Recherche des Cordeliers, INSERM, CNRS SNC 5096, Sorbonne Université, Université Paris Cité, Paris, France; Institut du cancer Paris CARPEM, AP-HP, Hopital européen Georges Pompidou, Paris, France.
²⁰ AGEO (Association des Gastroentérologues Oncologues), Paris, France; Centre de Recherche des Cordeliers, INSERM, CNRS SNC 5096, Sorbonne Université, Université Paris Cité, Paris, France; Institut du cancer Paris CARPEM, AP-HP, Hopital européen Georges Pompidou, Paris, France; Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France.

PMID: 37390800
DOI: 10.1016/j.ejca.2023.05.022

Abstract

Purpose: Baseline circulating tumour DNA (ctDNA) is a potential prognostic marker in metastatic colorectal cancer (mCRC) patients. However, few studies have compared ctDNA with the usual prognostic factors, and no ctDNA cut-off has been proposed for daily use in clinical practice.

Patients and methods: Chemotherapy-naive patients with mCRC were prospectively included. Plasma samples were collected at diagnosis and analysed centrally by both NGS and methylation digital PCR. Baseline patient and disease characteristics, treatment regimens, and secondary surgeries were collected. The restricted cubic spline method was used to define the optimal cut-off of ctDNA mutated allelic frequency (MAF). Prognostic values were assessed on overall survival (OS) using Cox models.

Results: From July 2015 to December 2016, 412 patients were included. ctDNA was undetectable in 83 patients (20%). ctDNA was an independent prognostic marker for OS considering the whole study population. The optimal cut-off for ctDNA MAF was 20% with median OS of 16.0 and 35.8 months for patients with MAF ≥20% and<20%, respectively (hazard ratio = 0.40; 95% confidence intervals: 0.31-0.51; P < 0.0001). The independent prognostic value of ctDNA MAF at 20% was confirmed in subgroups defined by RAS/BRAF status or resectability of metastases. Combining ctDNA MAF and carcinoembryonic antigen levels allowed us to define three different prognostic groups with median OS of 14.2, 21.1, and 46.4 months (P < 0.0001).

Conclusion: ctDNA with a MAF cut-off of 20% improves prognostication of chemotherapy-naïve mCRC patients and may be useful in the future for individualised therapeutic decisions and as a stratification factor in clinical trials.

Trial registration: Clinicaltrials.gov, NCT02502656.

Keywords: BRAF; CEA; Circulating tumour DNA; Colorectal cancer; Metastases; Prognostic value; RAS.

Publication types

Clinical Study
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / genetics
Circulating Tumor DNA*
Colonic Neoplasms*
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / pathology
Humans
Mutation
Prognosis
Prospective Studies
Rectal Neoplasms*

Substances

Biomarkers, Tumor
Circulating Tumor DNA

Associated data

ClinicalTrials.gov/NCT02502656