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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.

Author information

1
Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.
2
Department of Oncology, University of Torino, Candiolo, Torino, Italy.
3
Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano, Milan, Italy.
4
Department of Oncology and Haematology-Oncology, University of Milan, Milano, Milan, Italy.
5
Guardant Health, Inc., Redwood City, California.
6
The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
FIRC Institute of Molecular Oncology (IFOM), Milano, Milan, Italy.
8
Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano, Milan, Italy. alberto.bardelli@unito.it salvatore.siena@unimi.it.
9
Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy. alberto.bardelli@unito.it salvatore.siena@unimi.it.
#
Contributed equally

Abstract

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 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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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).

CONCLUSIONS:

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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