ctDNA Analysis in ERBB2-Amplified Colorectal Cancer: Biomarker Analysis of the MyPathway Trial

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.