Abstract
PurposeHuman epidermal growth factor receptor 2 (HER2) status is both an independent prognostic factor and a predictive factor for the efficacy of targeted therapy for breast cancer, so it is critical to accurately detect HER2 protein expression and/or gene amplification. According to the recommendations of the 2013 American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) guidelines for HER2 breast cancer testing, an additional test should be pursued on a different block from the same tumor as one of the options for patients with immunohistochemistry (IHC) 2+ and a HER2/CEP17 ratio of < 2.0 with an average HER2 signals per tumor cell of ≥ 4.0 and < 6.0 by reflex test using dual-probe fluorescence in situ hybridization (FISH) (double-equivocal HER2). Our aim in this study is to explore the consistency of HER2 status between the two blocks.MethodsWe retrospectively analyzed 5685 primary invasive breast cancers between April 2015 and January 2019 from Peking Union Medical College Hospital. For cases with double-equivocal HER2 revealed in initial blocks, HER2 gene status was evaluated by FISH in a different block from the same tumor. The FISH score was interpreted according to the 2013 ASCO/CAP guidelines for HER2 testing.ResultsIn our cohort of 5685 specimens, the overall HER2 IHC3+, 2+, 1+ and 0 cases were 20.5%, 31.8%, 28.3%, and 19.5%, respectively. Then, 13.7%, 66.3%, and 20.0% of HER2 amplification, non-amplification, and equivocation rates were found, respectively, in IHC2+ patients (n = 1777) by reflex FISH assay. For specimens with double-equivocal HER2 (n = 333), HER2 status was assessed in another block from the same tumor by FISH and then the frequency of HER2 positive, negative, and equivocation was estimated at 5.7%, 22.5%, and 71.8%, respectively. Because double-equivocal HER2 cases are classified in the HER2 negative category by the 2018 ASCO/CAP HER2 testing guidelines, only 1.3% (19/1511) of HER2 positive patients were determined through additional HER2 testing in another block from the HER2 negative population.ConclusionsHER2 status in different blocks from the same tumor in primary invasive breast cancer was highly concordant. Our data supported the recommendation of the 2018 ASCO/CAP HER2 testing guidelines in breast cancer to remove the suggestion for additional HER2 testing using another block contained in the previous version.
Highlights
Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein that plays a key role in the regulation of cell growth, apoptosis, and differentiation, so overactivity of HER2 will lead to malignant biological behavior in the breast [1]
1777 IHC2+ cases were analyzed by reflex fluorescent in situ hybridization (FISH) test (30 HER2 IHC-equivocal cases failed to be re-tested for various reasons) for determining HER2 status
Of 333 HER2 double-equivocal cases analyzed by reflex FISH testing (22 HER2 double-equivocal cases failed to be tested because no additional blocks were available) using another formalin-fixed paraffin-embedded (FFPE) block from the same tumor, 19 (5.7%, 19/333) positive, 75 (22.5%, 75/333) negative, and 239 (71.8%, 239/333) equivocation of HER2 status were found (Fig. 1)
Summary
Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein that plays a key role in the regulation of cell growth, apoptosis, and differentiation, so overactivity of HER2 will lead to malignant biological behavior in the breast [1]. HER2 gene amplification and/or protein overexpression occurs in approximately 25–30% of invasive breast cancer [2, 3]. Studies show that HER2 is an independent factor of poor prognosis, and a crucial predictive factor for the response to treatment, especially for anti-HER2 targeted therapy, e.g., trastuzumab, pertuzumab, lapatinib, and Trastuzumab–emtansine, which have been demonstrated to produce responses in breast cancers showing an HER2-positive feature [4]. It is necessary to accurately determine HER2 status for each breast cancer patient. One is immunohistochemistry (IHC) for HER2 protein expression examination, and another is fluorescent in situ hybridization (FISH) for HER2 gene amplification examination. In most laboratories in China, IHC analysis is generally used as a primary screening for HER2 status, and the reflex test would be performed by FISH for HER2 IHC2+ cases, both assays were implemented simultaneously in a small number of laboratories
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