Faculty Collaboration Database

ctDNA Analysis in ERBB2-Amplified Colorectal Cancer: Biomarker Analysis of the MyPathway Trial. Clin Cancer Res 2025 Jul 15;31(14):2935-2944

Date

06/13/2025

Pubmed ID

40512191

Pubmed Central ID

PMC7618057

DOI

10.1158/1078-0432.CCR-24-2763

Scopus ID

2-s2.0-105011600837 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

PURPOSE: A combination of two HER2-directed antibodies, pertuzumab and trastuzumab (P + T), has antitumor activity in HER2-positive colorectal cancer. Although liquid biopsies are increasingly being used in clinical oncology, the association between tumor and ctDNA ERBB2 status and ctDNA monitoring for early response and resistance are unknown.

PATIENTS AND METHODS: Eighty-five patients with ERBB2-amplified and/or -overexpressed colorectal cancer were treated with P + T in the MyPathway trial; 42 had ctDNA testing at cycle (C) 1 day (D) 1, and 38 had longitudinal plasma tested for ctDNA. We analyzed the ctDNA versus tissue ERBB2 concordance, genomic co-alterations, and ctDNA dynamics and association with response.

RESULTS: Forty-one (98%) of 42 patients had genomic alterations detected in ctDNA at C1D1, and 29 (69%) had ERBB2 amplification in ctDNA. There was a strong correlation between the ERBB2 copy number on next-generation sequencing in tissue and C1D1 ERBB2 ctDNA copy number. Thirty-seven percent achieved a molecular response by C3D1 on P + T, which was associated with prolonged progression-free survival and overall survival. CDKN2A and KRAS mutations were associated with shorter overall survival, and a trend was seen with PIK3CA mutations. Several emerging co-alterations were identified in ctDNA at progression, including in the MAPK and PI3K pathways and other tyrosine receptor kinases.

CONCLUSIONS: ctDNA can detect ERBB2 amplification in many, but not all, patients with ERBB2 amplification detected in tumor samples. ctDNA molecular response was associated with better survival, and ctDNA co-alterations may offer insights into mechanisms of intrinsic and acquired resistance.

Author List

Meric-Bernstam F, Raghav KPS, Sweeney CJ, Swanton C, Spigel DR, Bose R, Burris HA, Friedman CF, Espenschied CR, Grindheim JM, Malato J, Schulze K, Price R, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols
Biomarkers, Tumor
Circulating Tumor DNA
Colorectal Neoplasms
Female
Gene Amplification
High-Throughput Nucleotide Sequencing
Humans
Liquid Biopsy
Male
Middle Aged
Mutation
Receptor, ErbB-2
Trastuzumab