Higher densities of tumour‐infiltrating lymphocytes and CD4⁺ T cells predict recurrence and progression of ductal carcinoma in situ of the breast

Abstract

AimsHost immunity influences cancer progression and therapeutic response. We investigated the potential of tumour‐infiltrating lymphocytes (TILs) around ductal carcinoma in situ (DCIS) in predicting recurrence and progression.Methods and resultsCD4, CD8, programmed cell death 1 (PD‐1) and programmed cell death ligand 1 (PD‐L1) expression in DCIS from 198 patients was determined by immunohistochemistry. We correlated disease‐free survival (DFS), clinicopathological parameters and biomarker expression with TIL density and CD4/CD8 ratio. High TIL density was associated with high nuclear grade (P < 0.001), DCIS PD‐L1 expression (P = 0.008), TIL PD‐L1 expression (P < 0.001), oestrogen (ER) negativity (P < 0.001), progesterone (PR) negativity (P < 0.001), human epidermal growth factor receptor 2 (HER2) positivity (P = 0.002) and triple negativity (P = 0.001). TIL PD‐L1 expression was associated with triple‐negative DCIS (P = 0.028). TIL density was associated with molecular subtypes (P < 0.001). High CD4+ T cell density was associated with high nuclear grade (P = 0.001), microinvasion (P = 0.037), ER negativity (P < 0.001), PR negativity (P = 0.001), HER2 positivity (P = 0.004), triple negativity (P = 0.023) and PD‐L1 expression in TILs (P < 0.011). High CD4/CD8 ratio was associated with PD‐L1 expression in DCIS (P = 0.035) and TILs (P < 0.001). DCIS with higher TIL density disclosed worse DFS (P = 0.012) and was affirmed with multivariate analysis [95% confidence interval (CI) = 1.109–2.554, hazard ratio (HR) = 1.683, P = 0.014]. Poorer DFS for ipsilateral invasive recurrence was found for DCIS with higher CD4+ T cell density (P = 0.006) or CD4/CD8 ratio (P = 0.02), confirmed by multivariate analysis for the former (95% CI = 1.369–10.196, HR = 3.736, P = 0.01) and latter (95% CI = 1.311–7.935, HR = 3.225, P = 0.011).ConclusionDCIS with higher TIL density was associated with poorer prognostic parameters and predicted recurrence, while both CD4+ T cell density and CD4/CD8 ratio were associated with both recurrence and ipsilateral invasive recurrence.

Tumour‐infiltrating lymphocytes in ductal carcinoma in situ (DCIS)—assessment with three different methodologies and correlation with Oncotype DX DCIS Score

“…19 However a more recent study, which examined a cohort of 198 patients with known recurrence, demonstrated a significant association between circumferential TILs (defined as three layers of TILs surrounding ≥25% of the duct circumference) and worse disease-free survival (P = 0.012). 20 In our current study, in multivariate analysis, with adjustment for nuclear grade and necrosis, both touching TILs and circumferential TILs showed significant associations with an intermediate/ high ODX DCIS Score. Conversely, stromal TILs, which could be up to two high-power fields from the DCIS, did not show a significant association with an intermediate/high ODX DCIS Score in multivariate analysis.…”

“…One similar report did not find a significant association between circumferential TILs and a high ODX DCIS Score, but that study examined only 37 cases, and even in that small cohort there was a trend towards significance ( P = 0.096) 19 . However a more recent study, which examined a cohort of 198 patients with known recurrence, demonstrated a significant association between circumferential TILs (defined as three layers of TILs surrounding ≥25% of the duct circumference) and worse disease‐free survival ( P = 0.012) 20 . In our current study, in multivariate analysis, with adjustment for nuclear grade and necrosis, both touching TILs and circumferential TILs showed significant associations with an intermediate/high ODX DCIS Score.…”

Prognostic and predictive significance of tumor infiltrating lymphocytes for ductal carcinoma in situ

“…22 Low CD8 + T cells, high FOXP3 + regulatory T cells, high numbers of B cells, and high density of CD68+ and CD163+ macrophages have been validated to be associated with increased recurrence risk in the DCIS population. 12,22,36,37 After a retrospective analysis of 117 DCIS patients, Campbell et al found that not only high cytotoxic T lymphocytes (CTL) but also high numbers of CD115 + macrophage cells were predictive of high recurrence risk. 38 A study with subset analysis of TILs has shown an association between low CD8+/FOXP3+ ratio and high risk of ipsilateral recurrence.…”

Clinicopathological characteristics and prognostic analysis of tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ (DCIS) and DCIS with microinvasion (DCIS-Mi) of the breast

“…Similarly, they confirmed that "Touching-TILs" > 5 is an independent prognostic factor for higher ipsilateral breast tumor recurrence (IBTR). Based on different TILs evaluation criteria, many studies [22,23] have confirmed that highdensity TILs is associated with poor prognostic parameters and predicting recurrence of DCIS. Moreover, the cut-off values for the risk stratification of TILs in the current study are quite different.…”