Two progressive pathways of microinvasive carcinoma: low-grade luminal pathway and high-grade HER2 pathway based on high tumour-infiltrating lymphocytes

Morita, Michi; Yamaguchi, Rin; Tanaka, Maki; Tse, Gary M.; Miki, Yoshio; Otsuka, Hiroko; Kanomata, Naoki; Minami, Shigeki; Eguchi, Susumu; Yano, Hirohisa

doi:10.1136/jclinpath-2015-203506

Cited by 21 publications

(12 citation statements)

References 24 publications

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“…Some authors postulated associations between tumour infiltrating T-cell quantity and ER-as well as PR-negativity [40], which is in accordance with our results, while others did not [41]. Research into microinvasive breast cancer provided a hypothesis on immunogenicity of HER2-overexpressing tumours, which leads to the accumulation of cytotoxic T-cells, and, finally, to the rupture of the basement membrane [42]. Moreover, among luminal lesions, we noted that T-cells located at the invasive front of malignant lesions were the only subpopulation that differed significantly, with their highest density in luminal B/HER2+ lesions.…”

Section: Discussionsupporting

confidence: 91%

Lymphoid environment in molecular subtypes of breast cancer

Glajcar¹,

Szpor²,

Tyrak³

et al. 2018

pjp

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Recently, a large body of evidence has shown that the microenvironment of invasive breast carcinoma affects its development and the patient's outcome, and vice versa-cancer cells express factors that modulate tumour milieu in terms of its composition and function. We performed an immunohistochemical (IHC) staining of 108 formalin-fixed, paraffin-embedded (FFPE) tissue samples to investigate the relationships between T-cell, B-cell, and NK-cell infiltrate, invasive breast carcinomas molecular subtypes, and other prognostic indicators. The main findings of our study were as follows: the significantly higher infiltrate of the analysed immune cell subsets in triple-negative (TNBC), HER2-positive, non-luminal and luminal B/HER2+ breast carcinomas than in luminal A cancers; their higher densities in poorly differentiated lesions; correlations between lymphoid cells and the expression of hormonal receptors, HER2 receptor status, and marker of cancer proliferation. Furthermore, we observed T-cell numbers to be associated with greater tumour diameter. In summary, the results of our study indicate associations between tumoural lymphoid infiltration and the unfavourable intrinsic subtypes as well as other detrimental prognostic factors in invasive breast carcinomas.

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Section: Discussionsupporting

confidence: 91%

Lymphoid environment in molecular subtypes of breast cancer

Glajcar¹,

Szpor²,

Tyrak³

et al. 2018

pjp

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“…Supporting previous findings, our study has shown a significant association of high-TIL levels with triple-negative and HER2-positive subtypes of non-invasive breast cancer, which usually present high proliferation rates and high risk of invasion [ 16 , 21 , [35] , [36] , [37] ]. In previous studies, high-TIL levels have been observed in areas of microinvasive breast cancer, suggesting that more aggressive tumours may also be more immunogenic [ 12 , 36 , 38 , 39 ]. Additionally, the activation of the HER2 pathway seems to drive the tumoral stroma into a pro-immunogenic state, as HER2-positive tumours have a high frequency of CD8 + T cells and a low PD-L1 expression in their lymphocytic infiltrate [ 21 , 25 , [35] , [36] , [37] , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Tumour-infiltrating lymphocytes in non-invasive breast cancer: A systematic review and meta-analysis

et al. 2021

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Background: The role of tumour infiltrating lymphocytes (TILs) as a biomarker in non-invasive breast cancer is unclear. This meta-analysis assessed the prognostic impact of TIL levels in patients with noninvasive breast cancer. Methods: Systematic literature search was performed to identify studies assessing local recurrence in patients with non-invasive breast cancer according to TIL levels (high vs. low). Subgroup analyses per local recurrence (invasive and non-invasive) were performed. Secondary objectives were the association between TIL levels and non-invasive breast cancer subtypes, age, grade and necrosis. Odds ratios (ORs) and 95% confidence intervals (CI) were extracted from each study and a pooled analysis was conducted with random-effect model. Results: Seven studies (N ¼ 3437) were included in the present meta-analysis. High-TILs were associated with a higher likelihood of local recurrence (invasive or non-invasive, N ¼ 2941; OR 2.05; 95%CI, 1.03 e4.08; p ¼ 0.042), although with a lower likelihood of invasive local recurrence (N ¼ 1722; OR 0.69; 95% CI, 0.49e0.99; p ¼ 0.042). High-TIL levels were associated with triple-negative (OR 3.84; 95%CI, 2.23 e6.61; p < 0.001) and HER2-positive (OR 6.27; 95%CI, 4.93e7.97; p < 0.001) subtypes, high grade (OR 5.15; 95%CI, 3.69e7.19; p < 0.001) and necrosis (OR 3.09; 95%CI, 2.33e4.10; p < 0.001). Conclusions: High-TIL levels were associated with more aggressive tumours, a higher likelihood of local recurrence (invasive or non-invasive) but a lower likelihood of invasive local recurrence in patients with non-invasive breast cancer.

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“…10,11 The role of the immune response in DCIS is an area of interest; however, the association between density of TILs and DCIS recurrence has not been well established due to a variety of controversial data. 12,13 Assessment of stromal TILs, as detailed by the International Immuno-Oncology Biomarker Working Group, did not demonstrate an association with DCIS recurrence. [14][15][16] A more recent methodology of TILs assessment, which looked at TILs touching DCIS ducts (touching-TILs), was found to be an independent prognostic variable for LR in DCIS.…”

Section: Introductionmentioning

confidence: 94%

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

Zheng

Che

et al. 2021

OncoImmunology

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This study aims to identify the density of TILs in ductal carcinoma in situ (DCIS) in terms of prognostic significance with recurrence and the benefit of whole breast irradiation (WBI). The clinicopathological data of DCIS patients from Jan 2009 to Dec 2016 who received breast-conserving surgery (BCS) were retrospectively reviewed. Cox regression analysis was used to confirm independent prognostic factors of ipsilateral breast tumor recurrence (IBTR). Kaplan-Meier method was utilized to analyze IBTR and values of WBI. Touching-tumor-infiltrating lymphocytes (TILs) were defined by TILs touching or within one lymphocyte cell thickness from the malignant ducts' basement membrane. In total, 129 patients were enrolled in this analysis with 98 patients who received WBI. After a median follow-up of 53.0 months, there were 16 IBTR events with five invasive IBTRs. Univariate and multivariate analyses showed that touching-TILs >5 were an independent prognostic factor for higher IBTR (HR = 6.17, 95%CI 1.95-19.56, p < .01). The whole cohort was classified into two subgroups: dense group (>5 touching-TILs per duct) and sparse group (≤5 touching-TILs per duct). Dense touching-TILs were associated with unfavorable biologic characteristics. The 5-y rate of IBTR between dense and sparse group was 29.0% versus 4.5% (p < .01). For the sparse group, WBI significantly reduced the rate of 5-y-IBTR risk from 13.2% to 1.7% (p = .02), but there was no benefit of WBI in the dense group. Touching-TILs density was heterogeneous in patients with DCIS. Sparse touching-TILs were associated with better prognosis and benefit from WBI. Dense touching-TILs not only were associated with a higher risk of IBTR but also lack of benefit from WBI.

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Two progressive pathways of microinvasive carcinoma: low-grade luminal pathway and high-grade HER2 pathway based on high tumour-infiltrating lymphocytes

Cited by 21 publications

References 24 publications

Lymphoid environment in molecular subtypes of breast cancer

Lymphoid environment in molecular subtypes of breast cancer

Tumour-infiltrating lymphocytes in non-invasive breast cancer: A systematic review and meta-analysis

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

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