Collagen plays a key role in normal and malignant tissue homeostasis. While the prognostic significance of
collagen fiber remodeling in invasive
breast cancer has been studied, its role in
ductal carcinoma in situ (
DCIS) remains poorly defined. Using image analysis, we aimed to evaluate the prognostic significance of the geometric characteristics of
collagen surrounding
DCIS. A large well-characterized cohort of
DCIS comprising pure
DCIS (n = 610) and
DCIS coexisting with invasive
carcinoma (n = 180) were histochemically stained for
collagen using
picrosirius red. ImageJ software was used to assess
collagen density, degree of
collagen fiber dispersion and directionality in relation to
DCIS ducts' boundary. We developed a
collagen prognostic index and evaluated its prognostic significance. A poor index was observed in 24% of the pure
DCIS and was associated with determinants of high-risk
DCIS including higher nuclear grade, comedo type
necrosis, hormonal receptor negativity, HER2 positivity and high proliferation index. High
collagen prognostic index was associated with the
collagen remodeling
protein prolyl-4-hydroxlase alpha subunit 2 and the
hypoxia-related
protein hypoxia inducible factor 1α.
DCIS coexisting with invasive
breast cancer had a higher
collagen prognostic index than pure
DCIS ( p < 0.0001). High index was an independent poor prognostic factor for
DCIS recurrence for all recurrences (HR = 2.3, p = 0.005) and just invasive recurrences (HR = 3.4, p = 0.003). Interaction between
collagen prognostic index and
radiotherapy showed that the index was associated with poor outcome even with
adjuvant radiotherapy ( p = 0.0001).
Collagen reorganization around
DCIS is associated with poor outcome and provides a potential predictor for
disease progression and resistance to
radiotherapy. Mechanistic studies are warranted to decipher the underlying mechanisms.