Standardizing the pathologic assessment of HER2-(ultra)low breast cancer: insights from a national Italian project

Novel therapies for HER2-(ultra)low breast cancer (BC) have changed the traditional binary classification of HER2 status into a multi-tiered system that captures the full spectrum of expression as determined by immunohistochemistry (IHC). Several pre-analytical and analytical variables can influence the accurate identification of HER2 expression within the lowest IHC range.

Herein, we present the findings of a national Italian project addressing the diagnostic challenges associated with HER2-(ultra)low BCs and their proper classification.

A total of 121 pathologists from various regions and institutions were recruited and asked to: i) complete an online survey addressing key pre-analytical and analytical issues affecting HER2 status reporting in BC; ii) score 8 cases of IHC HER2-(ultra)low whole slide images (WSI) shared online; iii) participate in on-site meetings to discuss the results and evaluate 8 additional challenging WSIs. The assessments were subsequently compared to those of an expert panel.

Several pre-analytical and analytical concerns emerged from the questionnaire, such as reporting resection cold ischemia time and decalcification agent of choice and the employment of adequate HER2 controls. Regarding the WSIs, a substantial overall agreement (69%) with the expert panel was observed (74% in the online phase and 64% in the on-site phase), along with substantial to excellent consensus (≥ 61%) in over 60% of the samples. Most discordances emerged in the on- site cohort, which was enriched with challenging cases, particularly within the HER2 0+/ultralow spectrum, which demonstrated an overall agreement of 48%.

This nationwide study highlights the complexities of accurately classifying HER2-(ultra)low breast cancers, particularly within the HER2-ultralow subset. While a substantial level of agreement with expert assessments was achieved, the variability observed in more challenging cases underscores the need for standardized interpretation criteria, enhanced training, and continuous quality assurance measures.