PMID- 36376842 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20221118 IS - 1475-2867 (Print) IS - 1475-2867 (Electronic) IS - 1475-2867 (Linking) VI - 22 IP - 1 DP - 2022 Nov 15 TI - HER2 amplification by next-generation sequencing to identify HER2-positive invasive breast cancer with negative HER2 immunohistochemistry. PG - 350 LID - 10.1186/s12935-022-02761-1 [doi] LID - 350 AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2) positive breast carcinomas due to HER2 amplification are associated with aggressive behavior and a poor prognosis. Anti-HER2-targeted therapies are widely used to treat HER2-positive breast carcinomas with excellent outcomes. Accurate identification of HER2 amplification status in breast carcinomas is of important diagnostic and treatment value. Currently, HER2 amplification status is routinely determined by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) testing. This study will review our past HER2 data to determine and characterize discordant results between HER2 IHC and FISH. It will also determine a potential impact of HER2 amplification status by next-generation sequencing (NGS) on these patients. METHODS: We reviewed a total of 4884 breast carcinomas with coexisting HER2 IHC and HER2 FISH performed at our institution from 2010 to 2022. 57 cases also had a Next-Generation-Sequencing-based (NGS) gene panel performed. Given the advances in biostatic analysis pipelines, NGS methods were utilized to provide results on HER2 amplification status along with somatic mutations. RESULTS: While the majority (ranging from 98.5% with IHC score of 0 and 93.1% with IHC score of 1 +) of 4884 breast carcinomas had concordant results from HER2 IHC and HER2 FISH testing, a small percentage of patients (ranging from 1.5% in those with IHC score of 0, to 6.9% with IHC score of 1 +) had discordant results, with negative HER2 IHC and positive HER2 FISH results. These patients could be reported as HER2-negative breast carcinomas if only HER2 IHC testing has been performed according to a current cost-effective HER2 test strategy. 57 patients had HER2 amplification status determined by NGS, and all patients had concordant results between HER2 NGS and FISH tests. A HER2-amplified breast carcinoma by NGS had a negative IHC and a positive HER2 FISH result. This case was classified as a HER2-positive breast carcinoma, had anti-HER2-targeted therapy, and achieved a complete clinical response. CONCLUSIONS: A small percentage of HER2-positive breast carcinomas are unidentified because of a negative HER2 IHC based on our current cost-effective HER2 test strategy. It is not feasible and affordable in routine clinical practice to perform HER2 FISH for the cases with negative HER2 IHC (IHC score 0 and 1 +). Therefore, NGS assays capable of simultaneously detecting both somatic mutations and HER2 amplification could provide a more comprehensive genetic profiling for breast carcinomas in a clinical setting. Identification of HER2 amplification by NGS in HER2-positive breast carcinomas with negative HER2 IHC results is important since these cases are concealed by our current cost-effective HER2 test strategy with IHC first (for all cases) and FISH reflex (only for cases with IHC score of 2 +), and would offer the opportunity for potentially beneficial anti-HER2-targeted therapies for these patients. CI - (c) 2022. The Author(s). FAU - Morsberger, Laura AU - Morsberger L AD - Department of Pathology, Cancer Genetics Laboratory, Cytogenetics and Genomics Lab, Molecular Diagnostic Lab, JH Genomics, Genomic Medicine and Pathology, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD, 21205, USA. AD - The Johns Hopkins Genomics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. AD - Cytogenetics Laboratory, Johns Hopkins University Hospital, Baltimore, MD, 21205, USA. FAU - Pallavajjala, Aparna AU - Pallavajjala A AD - Department of Pathology, Cancer Genetics Laboratory, Cytogenetics and Genomics Lab, Molecular Diagnostic Lab, JH Genomics, Genomic Medicine and Pathology, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD, 21205, USA. AD - The Johns Hopkins Genomics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. FAU - Long, Patty AU - Long P AD - Department of Pathology, Cancer Genetics Laboratory, Cytogenetics and Genomics Lab, Molecular Diagnostic Lab, JH Genomics, Genomic Medicine and Pathology, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD, 21205, USA. AD - The Johns Hopkins Genomics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. AD - Cytogenetics Laboratory, Johns Hopkins University Hospital, Baltimore, MD, 21205, USA. FAU - Hardy, Melanie AU - Hardy M AD - Department of Pathology, Cancer Genetics Laboratory, Cytogenetics and Genomics Lab, Molecular Diagnostic Lab, JH Genomics, Genomic Medicine and Pathology, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD, 21205, USA. AD - The Johns Hopkins Genomics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. AD - Cytogenetics Laboratory, Johns Hopkins University Hospital, Baltimore, MD, 21205, USA. FAU - Park, Rebecca AU - Park R AD - Department of Pathology, Cancer Genetics Laboratory, Cytogenetics and Genomics Lab, Molecular Diagnostic Lab, JH Genomics, Genomic Medicine and Pathology, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD, 21205, USA. AD - The Johns Hopkins Genomics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. AD - Cytogenetics Laboratory, Johns Hopkins University Hospital, Baltimore, MD, 21205, USA. FAU - Parish, Rebecca AU - Parish R AD - Department of Pathology, Cancer Genetics Laboratory, Cytogenetics and Genomics Lab, Molecular Diagnostic Lab, JH Genomics, Genomic Medicine and Pathology, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD, 21205, USA. AD - The Johns Hopkins Genomics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. AD - Cytogenetics Laboratory, Johns Hopkins University Hospital, Baltimore, MD, 21205, USA. FAU - Nozari, Azin AU - Nozari A AD - Department of Pathology, Cancer Genetics Laboratory, Cytogenetics and Genomics Lab, Molecular Diagnostic Lab, JH Genomics, Genomic Medicine and Pathology, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD, 21205, USA. AD - Cytogenetics Laboratory, Johns Hopkins University Hospital, Baltimore, MD, 21205, USA. FAU - Zou, Ying S AU - Zou YS AD - Department of Pathology, Cancer Genetics Laboratory, Cytogenetics and Genomics Lab, Molecular Diagnostic Lab, JH Genomics, Genomic Medicine and Pathology, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD, 21205, USA. yzou19@jhmi.edu. AD - The Johns Hopkins Genomics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. yzou19@jhmi.edu. AD - Cytogenetics Laboratory, Johns Hopkins University Hospital, Baltimore, MD, 21205, USA. yzou19@jhmi.edu. LA - eng PT - Journal Article DEP - 20221115 PL - England TA - Cancer Cell Int JT - Cancer cell international JID - 101139795 PMC - PMC9664724 OTO - NOTNLM OT - Breast cancer OT - Fluorescence in situ hybridization OT - HER2 amplification OT - HER2 immunohistochemistry OT - HER2-positive breast carcinoma OT - Next-generation sequencing COIS- The authors declare that they have no competing interest. EDAT- 2022/11/16 06:00 MHDA- 2022/11/16 06:01 PMCR- 2022/11/15 CRDT- 2022/11/15 00:10 PHST- 2022/07/15 00:00 [received] PHST- 2022/10/25 00:00 [accepted] PHST- 2022/11/15 00:10 [entrez] PHST- 2022/11/16 06:00 [pubmed] PHST- 2022/11/16 06:01 [medline] PHST- 2022/11/15 00:00 [pmc-release] AID - 10.1186/s12935-022-02761-1 [pii] AID - 2761 [pii] AID - 10.1186/s12935-022-02761-1 [doi] PST - epublish SO - Cancer Cell Int. 2022 Nov 15;22(1):350. doi: 10.1186/s12935-022-02761-1.