Abstract
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 noninvasive alternative. We determined the sensitivity of plasma copy number (pCN) for detecting ERBB2 amplifications and whether 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. Forty-eight pretreatment 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. Forty-seven of 48 samples had detectable ctDNA, and 46 of 47 samples were ERBB2-amplified on the basis of cfDNA [2.55-122 copies; 97.9% sensitivity (95% confidence interval, 87.2%-99.8%)]. An adjusted ERBB2 pCN of ≥25.82 copies correlated with BOR and PFS (P = 0.0347). cfDNA is a viable alternative to tissue-based genotyping in the metastatic setting. The cfDNA platform utilized correctly identified 28 of 29 (96.6%) of pretreatment 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 are proposed to select patients who will benefit from HER2-targeted therapy.
Highlights
Colon cancer is the third most common cancer worldwide, and approximately 20% of patients present with metastatic disease, which is associated with a poor prognosis and median overall survival (OS) of 24–30Note: Supplementary data for this article are available at Clinical Cancer Research Online.G
Forty-seven of 48 samples had detectable circulating tumor DNA (ctDNA), and 46 of 47 samples were ERBB2-amplified on the basis of cell-free DNA (cfDNA) [2.55–122 copies; 97.9% sensitivity (95% confidence interval, 87.2%–99.8%)]
An adjusted ERBB2 plasma copy number (pCN) of !25.82 copies correlated with best objective response (BOR) and progression-free survival (PFS) (P 1⁄4 0.0347)
Summary
Colon cancer is the third most common cancer worldwide, and approximately 20% of patients present with metastatic disease (metastatic colorectal cancer; mCRC), which is associated with a poor prognosis and median overall survival (OS) of 24–30Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).G. Colon cancer is the third most common cancer worldwide, and approximately 20% of patients present with metastatic disease (metastatic colorectal cancer; mCRC), which is associated with a poor prognosis and median overall survival (OS) of 24–30. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Bardelli are the co-senior authors of this article
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