Abstract 1607: An ERBB2 follow-on companion diagnostic for clinical care of patients with breast cancer
Authors: Yip Wai-ki , Skoletsky Joel , Ma Pei , Luo Jun , Milbury Coren , Burns Christine , Truesdell John , Elvin Julia , Otto Geoff , Lipson Doron , Ross Jeffrey , Miller Vincent , Stephens Philip , Doherty Michael , Vietz Christine , Sun James X. , Li Yali 
Published: August 2018

Abstract
Introduction: Patients with HER2-positive breast cancer may benefit from targeted therapies including trastuzumab and pertuzumab. While FDA has approved companion diagnostics (CDx) using FISH or IHC for identifying ERBB2 amplifications, molecular diagnostic testing in breast cancer is rapidly evolving towards comprehensive genomic profiling (CGP) due to an increasing number of biomarkers. However, clinical validity of ERBB2 testing in CGP has not yet been demonstrated in an FDA-approved manner. We present the first ERBB2 test using NGS as a follow-on CDx, which is part of FoundationOne CDx (F1CDx). Methods: Clinical validity was established against the FDA-approved HER2 FISH test, using retrospective breast cancer patient samples. For each sample, two tests using the FISH assay were performed, and clinical validity was established such that the F1CDx result is statistically non-inferior to the performance between two runs of FISH. Concordance was calculated on samples that agree between the two FISH tests. Results: Results are shown in Table 1. An exploratory analysis including low-level ERBB2 amplifications (CN=4; ploidy+2) detected by F1CDx demonstrated an improved PPA of 93.8%. A non-inferiority test demonstrated a margin of 8.0%. Further analysis showed that the discordance is most significant among samples with a low FISH ratio. In samples that are FISH-positive but F1CDx-negative, a second test of FISH only yields a FISH-FISH concordance of only 55%, suggesting significantly decreased FISH-FISH reproducibility. Conclusion: We presented a follow-on CDx for ERBB2. The F1CDx platform provides a single assay that identifies cancer patients who may be eligible to receive FDA-approved targeted therapeutics, conserves tissue by avoiding serial testing and can serve as clinical trial assay for studies requiring a molecular biomarker for eligibility. The data demonstrating clinical and analytical validity of ERBB2 may accelerate the use of CGP for routine clinical use.
Table 1. The ERBB2 companion diagnostic in FoundationOne CDxCompanion diagnosticERBB2 amplificationIndicated useTrastuzumab, ado-trastuzumab-emtansine, or pertuzumab in breast cancerApproved CDx comparatorHER2 FISH PharmDx® Kit (Dako Denmark A/S)Positive percent agreement (PPA)89.4% (101/113)Negative percent agreement (NPA)98.4% (180/183)Median unique sequence coverage&gt;500XPrecision100%Limit of Detection19.7% tumor content
Citation Format: Wai-ki Yip, Joel Skoletsky, Pei Ma, Jun Luo, Coren Milbury, Christine Burns, John Truesdell, Julia Elvin, Geoff Otto, Doron Lipson, Jeffrey Ross, Vincent Miller, Philip Stephens, Michael Doherty, Christine Vietz, James X. Sun, Yali Li. An ERBB2 follow-on companion diagnostic for clinical care of patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1607.