UK recommendations for HER2 assessment in breast cancer: an update

Abstract

The last UK breast cancer (BC) human epidermal growth factor receptor 2 (HER2) testing guideline recommendations were published in 2015. Since then, new data and therapeutic strategies have emerged. The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) published a focused update in 2018 that reclassified in situ hybridisation (ISH) Group 2 (immunohistochemistry (IHC) score 2+andHER2/chromosome enumeration probe 17 (CEP17) ratio ≥2.0 andHER2 copy number <4.0 signals/cell), as well as addressed other concerns raised by previous guidelines. The present article further refines UK guidelines, with specific attention to definitions of HER2 status focusing on eight key areas: (1) HER2 equivocal (IHC 2+) and assignment of the ASCO/CAP ISH group 2 tumours; (2) the definition of the group of BCs with low IHC scores for HER2 with emphasis on the distinction between IHC score 1+ (HER2-Low) from HER2 IHC score 0 (HER2 negative); (3) reporting cases showing HER2 heterogeneity; (4) HER2 testing in specific settings, including on cytological material; (5) repeat HER2 testing, (6) HER2 testing turnaround time targets; (7) the potential role of next generation sequencing and other diagnostic molecular assays for routine testing of HER2 status in BC and (8) use of image analysis to score HER2 IHC. The two tiered system of HER2 assessment remains unchanged, with first line IHC and then ISH limited to IHC equivocal cases (IHC score 2+) but emerging data on the relationship between IHC scores and levels of response to anti-HER2 therapy are considered. Here, we present the latest UK recommendations for HER2 status evaluation in BC, and where relevant, the differences from other published guidelines.

Improved concordance of challenging human epidermal growth factor receptor 2 dual in‐situ hybridisation cases with the use of a digital image analysis algorithm in breast cancer

“…The categorisation of five distinct HER2 ISH biological groups from the continuum of HER2 expression in the 2018 ASCO/CAP update highlighted the importance of accurate determination of HER2 status via IHC and ISH testing. Further research is required to evaluate whether these groups benefit from anti‐HER2 therapies to help inform treatment decisions in these patients 13,16–18 . We undertook subgroup analysis to evaluate if particular groups had higher levels of interobserver variability associated with their reporting.…”

“…Further research is required to evaluate whether these groups benefit from anti-HER2 therapies to help inform treatment decisions in these patients. 13,[16][17][18] We undertook subgroup analysis to evaluate if particular groups had higher levels of interobserver variability associated with their reporting. Low concordance was strikingly evident in group 2 and borderline group 5, as pathologist agreement was not significantly different from the agreement that may occur due to random chance.…”

Computational pathology in cancer diagnosis, prognosis, and prediction – present day and prospects

“…Current clinical pathways are based on the human interpretation of histopathology slides, and the role of AI algorithms in clinical practice needs to be ascertained. For example, invasive breast cancer is defined as HER2-positive if >10% of tumour cells show strong, complete membrane reactivity [60]. An AI algorithm could potentially distinguish between 8%, 10%, and 12% HER2-positive staining, something the human eye cannot discern.…”

HER2-low breast cancer: insights on pathological testing

“…ASCO/CAP (2013 version) ( 13 ) suggested that HER2 gene heterogeneity be defined as the presence of individual cell populations with different HER2 copy numbers and/or HER2/CEP17 ratios, accounting for at least 10% of the entire tumor cell population. The 2023 UK guidelines ( 14 ) for HER2 detection stated that at the level of HER2 protein expression, heterogeneity is defined as any cluster of cells (subclones) with strong or moderate expression of intact cell membranes in <10% of tumors; then the IHC score was 2+ and should be tested by in situ hybridization (ISH) ( Figure 1 ). If subclonal cells show weak staining in <10% of tumors that are otherwise regionally negative, the tumor is scored as 1+.…”