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 ¼ 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.
Plasma HER2 (ERBB2) copy number predicts response to HER2-targeted therapy in metastatic colorectal cancer / G. Siravegna, A. Sartore-Bianchi, R.J. Nagy, K. Raghav, J.I. Odegaard, R.B. Lanman, L. Trusolino, S. Marsoni, S. Siena, A. Bardelli. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 25:10(2019 May), pp. 3046-3053.
|Titolo:||Plasma HER2 (ERBB2) copy number predicts response to HER2-targeted therapy in metastatic colorectal cancer|
SIENA, SALVATORE (Penultimo) (Corresponding)
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Data di pubblicazione:||mag-2019|
|Data ahead of print / Data di stampa:||26-feb-2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1158/1078-0432.CCR-18-3389|
|Appare nelle tipologie:||01 - Articolo su periodico|