ERBB2 Comprehensive Profiling and Prognostication in Stage III Colon Cancer: Findings From PETACC8 and IDEA-France Cohorts

Camilla Pilati; Audrey Soulabaille; Claire Gallois; Hélène Blons; Anne Cayre; Marine Sroussi; Delphine Le Corre; Sophie Mouillet-Richard; Claire Mulot; Karine Le Malicot; Aurélien De Reynies; Jean-Baptiste Bachet; Christophe Borg; Frédéric Di Fiore; Rosine Guimbaud; Jaafar Bennouna; Thierry André; Julien Taieb; Frédérique Penault-Llorca; Pierre Laurent-Puig

doi:10.1053/j.gastro.2024.10.046

ERBB2 Comprehensive Profiling and Prognostication in Stage III Colon Cancer: Findings From PETACC8 and IDEA-France Cohorts

Gastroenterology. 2024 Nov 28:S0016-5085(24)05745-7. doi: 10.1053/j.gastro.2024.10.046. Online ahead of print.

Authors

Camilla Pilati¹, Audrey Soulabaille², Claire Gallois³, Hélène Blons³, Anne Cayre⁴, Marine Sroussi⁵, Delphine Le Corre², Sophie Mouillet-Richard², Claire Mulot², Karine Le Malicot⁶, Aurélien De Reynies², Jean-Baptiste Bachet⁷, Christophe Borg⁸, Frédéric Di Fiore⁹, Rosine Guimbaud¹⁰, Jaafar Bennouna¹¹, Thierry André¹², Julien Taieb¹³, Frédérique Penault-Llorca⁴, Pierre Laurent-Puig³

Affiliations

¹ Centre de Recherche des Cordeliers, Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France. Electronic address: camilla.pilati@inserm.fr.
² Centre de Recherche des Cordeliers, Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France.
³ Centre de Recherche des Cordeliers, Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France; Institut du Cancer Paris, Cancer Research for Personalized Medicine, Assistance Publique-Hôpitaux de Paris Centre, Hôpital Européen Georges Pompidou, Paris, France.
⁴ Department of Pathology, Centre Jean Perrin, UNICANCER, Institut National de la Santé et de la Recherche Médical, UMR 1240, Imagerie Moléculaire et Stratégies Théranostiques, University Clermont Auvergne, Clermont-Ferrand, France.
⁵ Centre de Recherche des Cordeliers, Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France; Institut Chimie Biologie Innovation, Laboratoire de BioChimie, École Supérieure de Physique et de Chimie Industriel, UMR 8231, Le Centre National de la Recherche Scientifique, Paris Sciences et Lettres University, Paris, France.
⁶ Fédération Francophone de Cancérologie Digestive, EPICAD Institut National de la Santé et de la Recherche Médical Lipides Nutrition Cancer, UMR 1231, University of Burgundy and Franche Comté, Dijon, France.
⁷ Centre de Recherche des Cordeliers, Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France; Department of Hepato-Gastroenterology, Groupe Hospitalier Pitié Salpêtrière, Paris, France; Association des Gastroentérologues Oncologues, Paris, France.
⁸ Department of Medical Oncology, University Hospital of Besançon, Besançon, France.
⁹ Hepatogastroenterology Department, Centre Hospitalier Universitaire Rouen, University of Rouen Normandy, INSERM 1245, Institut de Recherche en Oncologie Group, Normandie University, Rouen, France.
¹⁰ Digestive Medical Oncology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
¹¹ Thoracic Oncology Unit, University Hospital of Nantes and Institut National de la Santé et de la Recherche Médical, Regional Center for Research in Cancerology and Immunology, Nantes, France.
¹² Sorbonne Université and Hôpital Saint Antoine, INSERM 938, Site de Recherche Intégrée sur le Cancer Curamus, Paris, France.
¹³ Centre de Recherche des Cordeliers, Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France; Institut du Cancer Paris, Cancer Research for Personalized Medicine, Assistance Publique-Hôpitaux de Paris Centre, Hôpital Européen Georges Pompidou, Paris, France; Association des Gastroentérologues Oncologues, Paris, France.

PMID: 39612956
DOI: 10.1053/j.gastro.2024.10.046

Abstract

Background & aims: ERBB2 pathway activation, through amplification or activating mutations, represents a new target for colon cancer (CC) treatment. Molecular methods were compared with the gold standard for assessing ERBB2 status, and the prognostic value of ERBB2 amplification, mutations, and expression was determined using data from 2 phase 3 trials involving nearly 3000 patients with stage III CC.

Methods: In the PETACC8 trial, immunohistochemistry and fluorescence in situ hybridization, DNA, and RNA analysis were performed on 1813, 1719, and 1733 samples, respectively. In the IDEA-France trial, DNA and RNA sequencing was performed on 1129 and 1263 samples. The breast cancer SCAN-B cohort (n = 3409) served as an external reference. A new molecular ERBB2-amplified status was defined using ERBB2 next-generation sequencing score, RNA sequencing expression, and clustering based on ERBB2 neighboring gene expression. Concordance between diagnostic techniques and the association between time to recurrence (TTR) and ERBB2-status were evaluated.

Results: The prevalence of the molecular ERBB2-amplified group was 1.85% in PETACC8 and 1.5% in IDEA-France, with a concordance of 0.81 (95% CI, 0.70-0.92) with the gold standard immunohistochemistry and fluorescence in situ hybridization method in PETACC8. A nonlinear relationship was observed between TTR and ERBB2 expression, with extreme groups showing a less favorable prognosis (P < .0001) in both colon and breast cancers. Patients with molecular ERBB2-amplified status or mutations had the poorest prognosis, followed by low-expression and intermediate-expression groups (3-year TTR of 67.0%, 71.2%, and 77.9%, respectively). In multivariate analysis, the low-expression group had a significantly shorter TTR (hazard ratio, 1.28; 95% CI, 1.07-1.52).

Conclusions: The molecular definition of ERBB2 status could represent a cost-effective alternative in stage III CC. ERBB2 alterations and low RNA expression significantly reduced TTR, highlighting the complex role of ERBB2.

Keywords: ERBB2 Expression; HER2 Amplification; IHC/FISH; NGS Score; RNA-seq; Stage III CC Prognosis.