Biology or methodology?

In their article titled “Study of frequency and prognostic significance of HER2 overexpression by immunohistochemistry in high-risk endometrial cancer: A retrospective cohort study,” Gupta et al.[1] explored the impact of HER2 positivity, as determined by immunohistochemistry, on the prognosis of patients with endometrial cancer. Despite a trend toward a higher frequency of several adverse prognostic characteristics in the HER2-negative group compared to the HER2-positive group, there was no statistically significant difference in the median progression-free or overall survival times in this study.[1] The recently published DESTINY-PanTumor02 study showed that patients with endometrial cancer treated with trastuzumab deruxtecan had the numerically highest response rate compared with cohorts of other solid tumors.[2] This finding prompted us to search for an explanation for the lack of prognostic significance of HER2 overexpression in the study by Gupta et al. Methodological and biological factors should be considered a priori. Among methodological aspects, factors, such as small sample size, imprecision in estimation (as reflected in the wide 95% confidence intervals around survival outcomes), a high proportion of missing data on key outcomes, prognostic heterogeneity within both HER2-positive and HER2-negative groups, lack of information on follow-up time differences between groups, lack of matching, and other potential confounding variables, may skew survival estimates, necessitating caution when interpreting survival outcomes. Additionally, the exclusion of patients with follow-up times of less than 1 year raises the possibility that more aggressive forms of HER2-positive endometrial cancer were underrepresented in the comparison. For instance, in a randomized Phase II study, almost 40% (24 out of 61) of patients with advanced or recurrent serous uterine carcinoma who were not treated with trastuzumab died within the first year.[3] Regarding tumor biology, the negative prognostic role of HER2 positivity has not been demonstrated consistently across all tissue types in which it is used as a predictive biomarker. For example, in colorectal cancer, the prognostic impact of HER2 overexpression remains uncertain.[4,5] Further studies with larger sample sizes, matched groups, and comprehensive data are required to better understand the prognostic significance of HER2 overexpression in endometrial cancer. Despite some limitations, we believe that the article by Gupta et al.[1] is an important contribution to the overall body of knowledge on the role of HER2 in endometrial cancer. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.