TABLE 2.

Summary table listing the current challenges and future directions to improve HER2-low scoring.

Phase	Current challenges	Possible solutions
Pre-analytical	Variables influencing the IHC staining intensity: fixation, antigen retrieval, reaction time, temperature, and substrate concentration	Implementation and follow-up of strict SOPs, describing precisely the workflow
		Repeating the test for equivocal results may help to exclude technical problems
	The availability of different antibody clones with varying specificity	Updated guidelines that assess the reliability of commonly used HER2 IHC testing methods
Analytical	The subjective mode of HER2 assessment, observer variability	Rigorous quality control procedures and well-defined guidelines based on amplified clinical trials and patient recruitment to further educate pathologists for higher concordance in scoring
		Implementation of methodologies to improve HER2 assessment including machine learning approaches
	The heterogeneity of HER2 expression and/or amplification	Recruitment of further diagnostic approaches with a more precise cut-off
		Further investigation on whether the presence of intratumor heterogeneity may affect the efficacy of ADCs

Abbreviations: IHC, immunohistochemistry; SOPs, standard operating procedures; HER2, human epidermal growth factor receptor 2; ADC, antibody drug conjugate.