Digital analysis of spatial expression of stromal fibroblast activation protein alpha (FAP) in DCIS

INTRODUCTION: The presence of non-progressing ductal carcinoma in situ (DCIS) cases has raised concerns of overtreatment, necessitating comprehensive risk prediction. The tumour microenvironment, especially cancer-associated fibroblasts (CAFs), plays a key role in DCIS progression. Fibroblast activation protein alpha (FAP), a CAF biomarker, has shown prognostic potential, but its clinical significance and spatial organization in DCIS remain rarely discussed. METHODS: In this study, we employed a digital pathology pipeline to quantify stromal FAP expression and map its spatial organization. A total of 102 breast excision specimens were analysed, including pure DCIS and DCIS with co-existing invasive carcinoma (either nearby or distant). FAP expression was quantified and correlated with clinicopathological features and survival outcomes. RESULTS: Our results showed that FAP expression was significantly higher in DCIS with nearby invasion compared to DCIS with distant invasion (P = 0.014) and pure DCIS (P = 0.006), reaching levels comparable to the invasive component itself. Within these high-FAP regions, no expression gradient from the invasive front was observed. In multivariable analysis, high FAP expression (P = 0.053) and nuclear grade (P = 0.043) were associated with invasion in older patients (≥50 years). Additionally, high FAP expression correlated with high nuclear grade (P = 0.008), papillary DCIS (P = 0.029) and HER2-enriched subtype (P = 0.0497). Although FAP was not an independent predictor of overall survival, it showed a trend towards poorer survival when combined with invasion. CONCLUSIONS: In conclusion, FAP is a promising biomarker for predicting nearby invasive carcinoma. Its integration into the existing risk stratification models could enhance clinically meaningful prediction.