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

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 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 HER2targeted therapy.

Transcriptomic Analyses Revealed Systemic Alterations in Gene Expression in Circulation and Tumor Microenvironment of Colorectal Cancer Patients

“…ERBB2 copy number amplification was also evident in CRC liquid biopsies in patient plasma. Siravegna et al reported that when 3 or more copies of ERBB2 were found in circulation, this led to reduced progression free survival in 46 patients [51]. Even though we did not observe ERBB2 overexpression at the transcript level, upstream analysis shows it as a common denominator for several of our up-regulated transcripts, which suggest an activated state of ERBB2 in CRC.…”

Guardant360 Circulating Tumor DNA Assay Is Concordant with FoundationOne Next-Generation Sequencing in Detecting Actionable Driver Mutations in Anti-EGFR Naive Metastatic Colorectal Cancer

“…Immunohistochemistry and fluorescence in situ hybridization analysis are considered the standard assays to detect HER2 amplifications. HER2 amplification by ctDNA is dependent on both disease tumor burden and degree of HER2 amplification within the tumor . In the current study, 2 HER2 amplifications were detected on G360 testing, both of which were 1+ amplifications and were discordant with our F1 assay.…”

Preoperative detection of KRAS G12D mutation in ctDNA is a powerful predictor for early recurrence of resectable PDAC patients

“…26,27 Currently, the clinical utility of ctDNA is only approved in metastatic non-small-cell lung cancer (NSCLC) by FDA as a companion diagnostic, 28,29 while studies on many other cancers have also shown good prospects. [30][31][32][33][34][35][36] The fact that even little variability in process and analysis will result in completely different results restrains the further clinical utility of ctDNA. 37 In order to solve these problems, some projects, such as the European CANCER-ID, European Liquid Biopsy Academy (ELBA) and European Liquid Biopsy Society (ELBS) networks or the US-based BloodPAC, have been initiated.…”