The relationship between components of tumour inflammatory cell infiltrate and clinicopathological factors and survival in patients with primary operable invasive ductal breast cancer

Abstract

Background:The importance of the components of host local inflammatory response in determining outcome in primary operable ductal invasive breast cancer is not clear. The aim of this study was to examine the relationship between components of the tumour inflammatory cell infiltrate and standard clinicopathological factors including hormone status (oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER)-2), Ki-67 and survival in patients with primary operable invasive ductal breast cancer.Methods:Tumour inflammatory cell infiltrate, hormone status (ER, PR and HER-2), Ki-67 and standard clinicopathological factors were determined using routine pathological and immuno-histochemical techniques in 468 patients.Results:The large majority (94%) of ductal tumours had evidence of inflammatory cell infiltrate. The general inflammatory cell infiltrate was positively associated with high grade (P<0.001), the absence of ER (P<0.001), the absence of PR (P<0.01), the presence of vascular invasion (P<0.05) and high lymphocytic infiltrate, plasma cell infiltrate, other inflammatory cell infiltrate and macrophage infiltrate (all P<0.001). The median follow-up of the survivors was 165 months. During this period, 93 patients died of their cancer. On univariate analysis, stratified for ER status, tumour size (P<0.01), lymph node involvement (P<0.001), tumour plasma cell infiltrate (P<0.001), other inflammatory cell infiltrate (P<0.05) and treatment (P<0.05) were associated with poorer cancer-specific survival whereas lymphocyte infiltrate (P<0.001) was associated with improved cancer-specific survival. On multivariate analysis, stratified for ER status, lymph node involvement (P<0.05) was independently associated with poorer cancer-specific survival whereas increased tumour lymphocyte infiltrate (P<0.001) was independently associated with improved cancer-specific survival.Conclusion:The results of this study show that, using routine histology, the general inflammatory cell infiltrate was a common feature and was positively associated with high grade, the absence of ER, the absence of PR, the presence of vascular invasion and high-grade infiltration of lymphocytes, plasma cells, other inflammatory cells and macrophages. Also, that within a mature cohort of patients, a high lymphocytic infiltrate was associated with improved survival, independent of clinicopathological characteristics including ER status, in primary operable ductal invasive breast cancer. These results rationalise previous work and provide a sound basis for future studies in this important area of breast cancer research.

Tertiary lymphoid structures: prognostic significance and relationship with tumour-infiltrating lymphocytes in triple-negative breast cancer

“…Slides were histopathologically analysed for (i) TILs (defined as the mean percentage of stroma of invasive carcinoma infiltrated by lymphocytes and plasma cells in 10% increments; if <10% of stroma was infiltrated by TILs, 1% or 5% criteria were used; all available full sections were evaluated);1 19 (ii) the amount of inflammatory cells evaluated at the tumour's invasive margin (according to Klintrup criteria; score 0, no inflammatory cells at the invasive margin; score 1, mild and patchy increase of inflammatory cells; score 2, increased inflammatory cells forming a band-like infiltration at the invasive margin; score 3, prominent inflammatory reaction forming a cup-like zone at the invasive margin);6 20 (iii) aggregation of lymphoid cells in terminal duct lobular units (TDLUs; within 5 mm and >5 mm from the invasive or in situ carcinoma); (iv) the amount of TLSs in adjacent tissue including the in situ component (none, no TLS formation in the area adjacent to the tumour; little, TLSs occupying an area of <10% of the circumference of the tumour; moderate, 10–50%; or abundant, >50%; shown in figure 1); (v) the presence or absence of a germinal centre in TLSs; (vi) the percentage of tumour stroma in the most invasive tumour area (high percentage of tumour stroma, >50%; low percentage of tumour stroma, ≤50%);16 (vii) heterogeneity of the tumour (heterogeneous: invasive tumour mixed with normal breast parenchyma; homogeneous: invasive tumour mass without normal breast parenchyma); (viii) histological subtype and grade, percentage of in situ component, tumour size, pT stage, pN stage and lymphovascular invasion. Lymphoid aggregation with vessels showing HEV features (plump, cuboidal endothelial cells) with or without germinal centres was considered a TLS.…”

The association of tumor lymphocyte infiltration with clinicopathological factors and survival in breast cancer

“…Some data suggest thathighlevelsofTILsarealsoassociatedwithbetteroutcomesinHER2-positivebreastcancerpatients treatedwithtrastuzumabaswellasdualtrastuzumab and lapatinib with chemotherapy [7,11]. These findingsweresupportedbythelargephaseIIIBIG 02-98trial.ApositiveassociationbetweenTILsand survival independent of clinicopathological characteristics in primary operable ductal invasive breast cancerwasdescribedbyMohammedet al [16].High levels of TILs correlate with increased disease-free survival (DFS) after adjuvant anthracycline-based chemotherapy [13].IntheECOGtrials(E2197and E1199)multivariableanalysisconfirmedTILstobe an independent prognostic marker of DFS, DRFI (distantrecurrence-freeinterval)andOS(overallsurvival) for TNBCs. In this group higher TIL scores wereassociatedwithbetterprognosis;forevery10% increase in TILs, a 14% reduction of risk of recurrenceordeath(p =0.02),an18%reductionofrisk ofdistantrecurrence(p =0.04),anda19%reduction ofriskofdeath(p =0.01)weredescribed [19].As fornow,thestrongestassociationofTILsandbreast cancer outcome has been observed for TNBC patients who received adjuvant anthracycline-containing chemotherapy.…”

“…In previous analysis general inflammatory cellinfiltrationwasassociatedwithhighgrade,negativesteroid(ERandPR)receptorstatusandthepresenceofvascularinvasion [16].AhigherlevelofTILs wasdescribedinbreastcancerwithhigherdifferentiation,negativehormonereceptorstatusandHER2 overexpression [7]. An association between BRCA1 mutation and TILs was detected in ovarian cancer [17].Theauthorsdidnotfindsuchanassociationfor breast cancer.…”

Predictive and Prognostic Role of Tumor-Infiltrating Lymphocytes for Early Breast Cancer According to Disease Subtypes: Sensitivity Analysis of Randomized Trials in Adjuvant and Neoadjuvant Setting

“…Furthermore, the presence of TILs can influence the prognosis of BC patients. In this regard, large series of data suggest that tumors with higher TIL counts are associated with good prognosis in contrast with those with lower TILs [13][14][15]. However, in single studies, the prognostic effect was mostly robust in triple-negative BC (TNBC) and less well-established in other subtypes [16][17][18][19].…”