Breast cancer is the leading cause of cancer-associated deaths in women, primarily due to distant metastasis. Fibroblast Growth Factor Inducible 14 (TNFRSF12A or Fn14), is a type 1 cell surface receptor overexpressed in the majority of invasive breast cancers and not in normal breast epithelium. Our functional studies in-vitro show that Fn14 is a strong promoter of breast cancer cell invasion. We have also shown that overexpression of Fn14 correlates with clinical markers of breast cancer progression. The clinical significance of Fn14 as a prognostic biomarker, however, has not been explored.
We utilised a combined cohort of 2116 breast cancer patients to validate associations between Fn14 expression and additional clinically-relevant factors. We then evaluated the independent prognostic value of Fn14 as a biomarker of Distant Metastasis-Free Survival (DMFS) and determined whether Fn14 expression can improve prognostic accuracy by further stratifying breast cancer subtypes into clinically significant metastatic risk groups.
Fn14 expression was significantly associated with tumours defined immunohistochemically as ER-negative (p < 0.0001), HER2-positive (p < 0.001) or Triple-Negative (TNBC) (p < 0.031). Further associations were observed for tumours intrinsically defined as Basal-like (p < 0.0001) or HER2-enriched (p < 0.0001). No association was observed for Luminal A or B (ER-positive) tumours. Multi-variable Cox proportional hazards modelling revealed that patients in the upper tertile of Fn14 expression, compared to the lower tertile, had an increased risk of metastasis when major clinical factors were held constant (HR 1.83 [95% CI 1.49-2.25]; p = 0.004). Survival analysis revealed that Fn14 expression improved the prognostic accuracy of DMFS in hormone receptor-negative (ER p = 0.022, PR p < 0.005), HER2-positive (p = 0.007), and TNBC (p = 0.025) patients by significantly stratifying them into further risk groups, with higher Fn14 expression tertiles correlating with poorer DMFS.
These findings indicate that Fn14 is a significant independent prognostic biomarker of DMFS that warrants further investigation in patients with ER-negative, HER2-positive, and TNBC disease.