The relationship between the coagulation and inflammatory phases of wound healing in early breast cancer
Singh, U Castle, John Shaker, H. Greenhalgh, S. Hussain, U. Descamps, Tine Nash, S. Wilson, M. Hunt, R Kirwan, Cliona C
Singh, U
Castle, John
Shaker, H.
Greenhalgh, S.
Hussain, U.
Descamps, Tine
Nash, S.
Wilson, M.
Hunt, R
Kirwan, Cliona C
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Abstract
Introduction: Cancer is likened to a non-healing wound. Markers of
coagulation (TF, thrombin, PAR1 and PAR2), the fi rst phase of wound
healing, have increased stromal fi broblast expression in poor prognosis
breast cancer (estrogen receptor (ER) negative, Her2 positive, high
Ki67/grade). We hypothesised that markers of infl ammation, the
second phase of wound healing, (CD68, macrophage marker; Heme
oxygenase 1 (HO-1), macrophage and cancer cell marker; fi broblast
activation protein (FAP), fi broblast marker) would correlate with
coagulation markers and predict poor prognosis in early breast cancer.
Aim: To assess the relationship between coagulation and infl ammatory
markers in early breast cancer. To assess the prognostic value of
CD68, HO-1 and FAP infl ammatory markers using clinicopathological
variables.
Materials and Methods: The prospective cohort study CHAMPion
(Cancer induced Hypercoagulability as a Marker of Prognosis)
recruited patients with ductal carcinoma in situ(DCIS) and invasive
breast cancer. In tissue microarrays of 201 invasive tumours, 58 DCIS
tumours and matched normal breast tissue distant from disease, CD68+
tumour associated macrophage(TAM)/CD68+ normal macrophage
(normal tissue), epithelial HO-1 and fi broblast FAP expression,
quantifi ed by immunohistochemistry(dichotomised: high/present vs low/absent), was correlated with tumour factors (grade, proliferation
(Ki67), ER, HER2); demographics, behavioural factors (smoking,
alcohol) and survival (disease-free survival (DFS), overall survival
(OS)). Correlation between coagulation and infl ammatory markers
was assessed using Cramer’s V correlation test (p<0.05).
Results: High CD68+ macrophage expression was more commonly
seen in invasive breast cancer, compared to DCIS, and normal tissue
(59%, 41% and 6%, respectively; p<0.001). In invasive cancer,
CD68+ TAM expression was increased with increasing tumour grade
(Grade 1: 42%, Grade 2: 58%, Grade 3: 72%; p=0.006), high Ki67
(71% vs 47%; p=0.004), ER negativity (79.4% vs 55.4%; p=0.01)
and HER2 (HER2 positive 81.8% vs HER2 negative 56.3%; p=0.03).
CD68+ TAM expression was higher in high grade compared to low/
intermediate grade DCIS (44% vs 31%, p=0.52). CD68+ TAM
expression was increased patients who self-reported alcohol intake
(non-drinker 43% vs drinker 62%; p=0.01). Positive HO-1 and FAP
expression was not associated with poor prognosis subgroups however
cancer cell expression of HO-1 was associated with shorter DFS (HR
3.22, p=0.027) and OS (HR 2.86, p=0.029). Cancer-associated
fi broblast (CAF) and tissue factor (TF) expression weakly correlated
with high CD68+ TAM expression (CV 0.12, p=0.09), cancer cell
HO-1 expression (CV 0.14, p=0.04) and CAF FAP expression (CV
0.15, p=0.03). In CAFs, PAR2 and FAP expression correlated (CV
0.14, p=0.04).
Conclusions: Tumour infl ammation, as assessed by high CD68+ TAM
expression is increased in poor prognosis breast cancer sub-types. The
association reported here between CD68 and alcohol is suggestive of a
mechanism for alcohol as a breast cancer risk factor. The correlation
between stromal coagulation (fi broblast TF) and infl ammation
highlights wound healing as potentially mechanistic in breast cancer
growth.
Description
Date
2021
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Singh U, Castle J, Shaker H, Greenhalgh S, Hussain U, Descamps T, et al. PO-75 The relationship between the coagulation and inflammatory phases of wound healing in early breast cancer. Thrombosis Research . 2021 Apr;200:S58.