Objective. 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. Material and methods. 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. Results. 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%. Conclusions. 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.
Standardizing the pathologic assessment of HER2-(ultra)low breast cancer: insights from a national Italian project
Marletta, Stefano;
2026-01-01
Abstract
Objective. 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. Material and methods. 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. Results. 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%. Conclusions. 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
