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Clin Cancer Res. 2019 May 15;25(10):3046-3053. doi: 10.1158/1078-0432.CCR-18-3389. Epub 2019 Feb 26.

Plasma HER2 (ERBB2) Copy Number Predicts Response to HER2-targeted Therapy in Metastatic Colorectal Cancer.

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Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.
Department of Oncology, University of Torino, Candiolo, Torino, Italy.
Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano, Milan, Italy.
Department of Oncology and Haematology-Oncology, University of Milan, Milano, Milan, Italy.
Guardant Health, Inc., Redwood City, California.
The University of Texas MD Anderson Cancer Center, Houston, Texas.
FIRC Institute of Molecular Oncology (IFOM), Milano, Milan, Italy.
Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano, Milan, Italy.
Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.
Contributed equally



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.

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