Plasma HER2 (ERBB2) copy number predicts response to HER2-targeted therapy in metastatic colorectal cancer

Purpose: ERBB2 (HER2) amplification is an emerging biomarker in colon cancer, conferring sensitivity to combination anti-HER2 therapy. Measurement of HER2 copy number is typically performed using surgical specimens, but cell-free circulating tumor DNA (ctDNA) analysis may be a non-invasive alternative. We determined the sensitivity of pCN for detecting ERBB2 amplifications and whether plasma copy number (pCN) correlated with tissue-detected copy number. We also assessed response to HER2-targeted therapy based on pCN and suggest a pCN threshold predictive of response. Experimental Design: Forty-eight pre-treatment and progression plasma samples from 29 HER2-positive patients in the HERACLES A clinical trial were tested using the Guardant360™ cfDNA assay. We correlated ERRB2 pCN with progression-free survival (PFS) and best objective response (BOR) and applied an adjustment method based on tumor DNA shedding using the maximum mutant allele fraction as a surrogate for tumor content to accurately determine the pCN threshold predictive of response. Results: 47/48 samples had detectable ctDNA and 46/47 samples were ERBB2-amplified based on cfDNA (2.55-122 copies; 97.9% sensitivity (95% CI = 87.2-99.8%). An adjusted ERBB2 pCN of ≥25.82 copies correlated with BOR and PFS (p=0.0347). Conclusions:cfDNA is a viable alternative to tissue-based genotyping in the metastatic setting. The cfDNA platform utilized correctly identified 28/29 (96.6%) of pre-treatment samples as ERBB2-amplified and predicted benefit from HER2-targeted therapy. In this study, an observed pCN of 2.4 and an adjusted pCN of 25.82 copies of ERBB2 is proposed to select patients who will benefit from HER2-targeted therapy.

https://ift.tt/2Nw4ywn