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

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.

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.

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.

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.