Gene Expression Biomarkers for Breast Ductal Carcinoma in Situ Recurrence Prediction

ABSTRACT Breast ductal carcinoma in situ (DCIS) is often overtreated due to a lack of robust prognostic and predictive tools. This study aimed to evaluate gene expression in a well‐characterised DCIS cohort to determine their clinical utility as biomarkers for ipsilateral recurrence. RNA was extracted from microdissected tissues from primary DCIS. A 129‐gene panel was analysed using NanoString in 174 DCIS cases (131 with no recurrence and 43 with recurrence). Association with recurrence was determined by Cox regression analyses. Validation was performed by immunohistochemistry. A new 7‐gene panel ( PBK, COL1A2, GSTM5, MMP2, MX1, SLC22A3 and ZEB1 ) was derived from the NanoString data but could not be validated in external datasets, including when stratified by radiotherapy treatment. Increased expression of ZEB1 alone was consistently significantly associated with longer recurrence‐free survival in discovery and validation cohorts (hazard ratios 0.56–0.71). Correlation between mRNA and protein expression showed the strongest association with peri‐ductal fibroblast expression. However, there was no association of ZEB1 protein expression in these cells with recurrence in an independent cohort. Existing multigene panels showed inconsistent associations with recurrence in the current cohort. Gene expression panels show limited reproducibility across cohorts, highlighting the need for prospective trials and context‐specific validation. ZEB1 mRNA emerges as a potential biomarker warranting further investigation for its clinical utility in guiding management decisions in DCIS.