Current Challenges for HER2 Testing in Diagnostic Pathology: State of the Art and Controversial Issues

Abstract

HER2 overexpression and anti-HER2 agents represent probably the best story of success of individualized therapy in breast cancer. Due to the important therapeutic implications, the issue under the spotlight has been, since ever, the correct identification of true HER2 positivity on tissue specimens. Eligibility to anti-HER2 agents is strictly dependent on the demonstration of HER2 overexpression (by immunohistochemistry) or of HER2 gene amplification by in situ techniques (fluorescence in situ hybridization, FISH), however there are controversial issues involving cases with “equivocal” HER2 status based on conventional techniques (about 20% of specimens). In terms of HER2 expression a major debate is the presence of full-length and truncated forms of the protein and controversial clinical data have been reported on the therapeutic implications of these HER2 fragments. In terms of HER2 gene assessment, the occurrence of amplification of the chromosome 17 centromeric region (CEP17) has been proven responsible for misleading HER2 FISH results, precluding anti-HER2 based therapy to some patients. Finally HER2 activating mutations have been recently described as a biological mechanisms alternative to HER2 gene amplification. In this review we will focus on the controversies that pathologists and oncologists routinely face in the attempt to design the most tailored treatment for breast cancer patients. We will focus on the HER2 gene and on the protein, both at technical and interpretational levels.

Identification of TargetableERBB2Aberrations in Head and Neck Squamous Cell Carcinoma

“…Of note, we identified four samples positive for HER2 gene amplification on sequencing whereas only two were identified by immunohistochemistry. This can potentially be ascribed to tumor heterogeneity for HER2 expression, which has been well described in literature 30,31 . It remains unclear whether these HER2 heterogeneous tumors are responsive to anti-HER2 therapy 31 .…”

The New Equivocal

“…Sapino et al 16 reviewed several European and US scoring paradigms in a study of 957 Italian patients with breast cancer with equivocal (2+) IHC. They found an even larger shift in categorization than our US cohort.…”

Gene Status in HER2 Equivocal Breast Carcinomas: Impact of Distinct Recommendations and Contribution of a Polymerase Chain Reaction-Based Method

“…Within the latter subgroup, discordant results between the two techniques were observed in up to 50% of cases. This is important in diagnostic practice because some have advocated the use of alternative methods [1] because of the occurrence of altered CEP17. MLPA is a PCRbased method that performs well on fragmented DNA and may be reliably implemented in routine practice; however, because this technique is based on DNA extraction, tissue morphology is lost, as is the genetic heterogeneity, potentially leading to underestimation of HER2 amplification.…”