الفهرس 
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Abstract
In the current study, we investigated the expression of Tspan6 in two groups of infiltrating duct carcinoma (NOS) composed of inflammatory (IBC) and non-inflammatory breast cancer cases. Image analysis techniques were used to evaluate the density of tumour infiltrating macrophages (TIMs), and four subtypes of tumour infiltrating lymphocytes (TILs) stained with CD20, CD4, CD8 and FOXP3 immune markers in the surrounding microenvironment. The expression of these markers was correlated to the clinicopathological parameters. Response to neoadjuvant chemotherapy and patient overall survival data were available in IBC group only.
This study included 109 IBC cases. Their age ranged from 34 to 85 years old with a median 58 years. Grade 1 and 2 tumours represented 44% while 56% of the tumours showed grade 3 differentiation. ER-positive BC comprised 40 out of 109 cases (36.7%), 30.3% were triple negative BC and 33% showed HER2 enriched BC. All cases were T4 stage.
A total number of 77 non-IBC cases were included in this study. Patient age ranged from 30 to 88 years with a median age of 51 years. Grade 1 and 2 tumours represented 75.3% of cases whereas 24.7% of the cases showed high grade tumours (19/77). Sixty percent of cases were ER-positive BC, 22.1% were triple negative BC and the remaining cases were HER2 enriched BC (18.2%). Thirteen percent (10/77) were T1 stage, 63.6% were T2 stage (49/77) and cases with T3 stage represented 23.4% of the cases (18/77). Early nodal status group (N0 and N1) represented 46.8% while advanced nodal status (N2 and N3) was seen in 53.2% of the cases.
Tspan6 showed positive membranous ± cytoplasmic expression in 130 out of 186 (69.9%) in the whole cohort (IBC+ non-IBC cases). In IBC cases, Tspan6 showed positive expression in 65 out of 109 cases (59.6%) while in non-IBC cases, Tspan6 positive expression was seen in 65 out of 77 cases (84.4%).
Positive Tspan6 expression in all NOS and IBC group was significantly associated with ER-positive molecular subtype (p=0.03 and 0.002, respectively). On the other hand, a hundred percent of HER2 enriched BC subtype showed positive Tspan6 expression in non-IBC group (p=0.003).
Highly significant difference in Tspan6 expression was noticed between IBC (59.6%) and non-IBC cases (84.4%) (p< 0.001). Positive Tspan6 expression was significantly associated with low grade tumours in all cases (75.5% of cases) (p=0.05).
Profiling of immune cells within the tumoural areas of microenvironment in IBC, immune cells showed higher density of CD68+ TIMs, CD4+, CD8+, FOXP3+ cells than CD20+ tumour infiltrating lymphocytes (TILs), respectively. Total and stromal immune cell profiling showed the same sequence except an increase of CD20+ TILs density over the FOXP3+ TILs. On the other hand, total density of immune cells in non-IBC group showed more density of CD68+ TIMs, CD8+, CD4+, CD20+ than FOXP3+ TILs, respectively.
In the whole cohort and non-IBC group, cases with ER-positive BC were significantly associated with high total density of CD20+ TILs (p= 0.003 & 0.01, respectively) compared to the other molecular subtypes.
Summary
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Low grade IBC cases were significantly associated with increased the median density of tumoural of CD20+ TILs (p=0.04), while high grade tumours were significantly associated with higher stromal median density of CD8+ TILs (p=0.04). In non-IBC tumours, advanced nodal status was significantly associated with higher total density of CD4+TILs (p=0.003).
Comparison of immune cell densities between IBC and non-IBC revealed increased median and mean total densities of CD4+ (p=0.002) and FOXP3+TILs (p<0.001) in IBC cases. On the other hand, median and mean total densities of CD68+TIMs and CD8+TILs were significantly higher in non-IBC group (p=0.02 and 0.01, respectively).
Positive expression of Tspan6 showed significant association with higher stromal density of FOXP3+ TILs in IBC group (p=0.03) and lower total density of CD68+ TIMs in non-IBC (p=0.03).
In IBC group, pathological response was achieved in 67% of cases while no evidence of response was seen in 33% of cases (non-responders). Two thirds (68.5%) of IBC cases with positive expression of Tspan6 showed features of pathological response to NACT (p=0.007). Absence of pathological response to chemotherapy was significantly associated with higher tumoural CD68+ TIMs density (p=0.02). Significant high total and tumoural densities of CD8+ TILs were seen in TNBC cases who achieved pathological response to NACT (p=0.03 and 0.02, respectively).
Data about overall survival (OS) were available for 104 out of 109 in IBC group. The period of follow up ranged from one to 137 months with a median of 33 months and a mean 42.3. Fifty cases (48%) died from breast cancer. Prolonged overall survival was noticed in cases with HER2 enriched BC (p<0.001) and in cases who achieved pathological response to NACT in univariate analysis (p=0.04). Multivariate cox regression analysis showed that response to therapy was an independent good prognostic factor (p=0.03). However, no impact of Tspan6 or other infiltrating immune cells on patient overall survival were detected.