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Plasma HER2 (ERBB2) Copy Number Predicts Response to HER2-targeted Therapy in Metastatic Colorectal Cancer
Giulia Siravegna1,2, Andrea Sartore-Bianchi3,4, Rebecca J Nagy5
1Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.
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.
Insights
Plasma cell-free DNA (cfDNA) analysis can detect ERBB2 (HER2) amplification in colon cancer, serving as a noninvasive alternative to tissue biopsy. This method accurately predicts response to HER2-targeted therapy in patients with metastatic disease.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genetics
Background:
- ERBB2 (HER2) amplification is a key biomarker in colon cancer, indicating sensitivity to anti-HER2 therapies.
- Traditional HER2 testing relies on surgical specimens, which can be invasive and may not reflect tumor heterogeneity.
- Cell-free circulating tumor DNA (ctDNA) analysis offers a noninvasive approach for detecting genomic alterations like ERBB2 amplification.
Purpose of the Study:
- To evaluate the sensitivity of plasma copy number (pCN) for detecting ERBB2 amplifications in colon cancer.
- To assess the correlation between plasma-detected and tissue-detected HER2 copy number.
- To determine a predictive threshold for HER2-targeted therapy response using pCN.
Main Methods:
- Analysis of 48 pretreatment and progression plasma samples from 29 HER2-positive patients using the Guardant360 cfDNA assay.
- Correlation of ERBB2 pCN with progression-free survival (PFS) and best objective response (BOR).
- Application of an adjustment method using mutant allele fraction to estimate tumor DNA shedding and determine a predictive pCN threshold.
Main Results:
- High sensitivity (97.9%) of cfDNA for detecting ERBB2 amplification, with 46 of 47 samples identified as amplified.
- Detectable ctDNA was present in 47 of 48 samples.
- An adjusted ERBB2 pCN of ≥25.82 copies significantly correlated with BOR and PFS (P=0.0347).
Conclusions:
- cfDNA analysis is a viable noninvasive alternative to tissue genotyping for ERBB2 amplification in metastatic colon cancer.
- The Guardant360 cfDNA assay accurately identified ERBB2-amplified samples and predicted therapeutic benefit.
- Proposed thresholds of observed pCN (2.4) and adjusted pCN (25.82) can aid in selecting patients for HER2-targeted therapy.
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