The prevalence and clinical relevance of tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ of the breast

Pruneri, Giancarlo; Lazzeroni, Matteo; Bagnardi, Vincenzo; Tiburzio, G. B.; Rotmensz, Nicole; DeCensi, Andrea; Guerrieri-Gonzaga, Aliana; Vingiani, Andrea; Curigliano, Giuseppe; Zurrida, Stefano; Bassi, Fabio; Salgado, Roberto; Eynden, Gert Van den; Loi, Sherene; Denkert, Carsten; Bonanni, Bernardo; Viale, Giuseppe

doi:10.1093/annonc/mdw623

Cited by 81 publications

(102 citation statements)

References 21 publications

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“…In addition, HER2-positive DCIS show a higher TIL score than HER2-negative DCIS. These findings are in agreement with previous studies of the immune microenvironment of DCIS, in which ER-negative tumors showed a trend towards higher immune infiltrates (22,26,27) and HER2 positive tumors were strongly associated with a higher stromal TIL count (22). Despite significant positive associations with histological features that portend a poor prognosis such as high nuclear grade, comedo necrosis, periductal myxoid stroma, ER negativity, and HER2 positivity, no significant association was found in our study between TILs and recurrence.…”

Section: Discussionsupporting

confidence: 92%

“…Disease recurrence following DCIS can occur after many years, and although the TIL cohort was enriched for cases with recurrence (30/138, 21.7%) and had a prolonged median follow-up of 89 months (range, 1-304 months), the lack of association between TILs and recurrence requires further investigation in a large cohort with substantial length of follow-up to enable a well-powered multivariate analysis. One such study also failed to find a correlation between TILs and DCIS recurrence (22). However, such analysis is complicated by the likely different implication of TILs in different intrinsic subtypes (28), the different types of lymphocytes present not distinguishable by H&E staining and the difficulty in getting enough cases to make subgroup analysis sufficiently powerful.…”

Section: Discussionmentioning

confidence: 99%

“…The percentage stromal TILs, defined as the percentage of stromal area covered by mononuclear inflammatory cells, was estimated in the specialized stroma surrounding DCIS-containing ducts (21,22). TIL data were obtained from TCGA invasive breast cancer data (n ¼ 887 with associated Level 3 Affymetrix SNP6 copy number data) using the "biospecimen_ slide_brca" file, excluding those with 0% tumor and averaging the TILs from cases with more than one slide.…”

Section: Assessment Of Tilsmentioning

confidence: 99%

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Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

Hendry

Pang

Byrne

et al. 2017

Clinical Cancer Research

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Purpose: The immune microenvironment of breast ductal carcinoma in situ (DCIS) has yet to be fully explored, and the relationship of immune cells to genetic features of DCIS is unknown.Experimental Design: We quantified tumor associated lymphocytes (TIL) and evaluated PD-L1 protein levels by immunohistochemistry in a cohort of pure DCIS (138 and 79 cases, respectively), some of which had copy number (n ¼ 55) and mutation data (n ¼ 20).Results: TILs were identified in the stroma surrounding DCIS (119/138, 86%) and present at a median TIL score of 5% (range, 0%-90%). Most DCIS were negative for tumor cell PD-L1 staining (89%), but 25% of cases were positive for immune cell staining. We observed that, as in invasive breast cancer, TILs and PD-L1 positivity were significantly greater in high-grade (P ¼ 0.002/0.035), ER-negative (P ¼ 0.02/0.02), and ERBB2-amplified tumors (P < 0.001/0.048). Comedo necrosis was significantly positively associated with TILs (P < 0.0001) but not with PD-L1. The TILs score was significantly higher in cases with TP53 mutation (P ¼ 0.03) but not with PIK3CA or GATA3 mutation. In the cases with copy number data, both the fraction of the genome altered and the number of telomeric imbalances were significantly positively correlated with TILs (both P < 0.001). This result strongly contrasted with invasive breast cancer data, where aneuploidy was not correlated to TIL levels.Conclusions: Although a small cohort, our data suggest a preliminary model by which the progression of DCIS to invasive carcinoma may involve an altered relationship of tumor copy number with the immune microenvironment, possibly by the immunoediting of the tumor. Clin Cancer Res; 23(17); 5210-7.Ó2017 AACR.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Assessment Of Tilsmentioning

confidence: 99%

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Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

Hendry

Pang

Byrne

et al. 2017

Clinical Cancer Research

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“…In the current analysis of TILs and their significance in DCIS, a significant association was identified between TILs and tumor grade, central necrosis, and negative ER and PR status. These findings are consistent with previous studies (21–23). …”

Section: Discussionsupporting

confidence: 94%

Possible predictive role of cancer/testis antigens in breast ductal carcinoma in�situ

Roguljic¹,

Spagnoli

António

et al. 2018

Oncol Lett

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Cancer/testis antigens (CTAs) are a large family of tumor-associated antigens expressed in human tumors of different histological origin, but not in normal tissues, with the exception of the testes and placenta. Numerous immunohistochemical studies have reported associations between CTA expression and a negative estrogen receptor (ER) status in breast tumors, and demonstrated that CTAs are frequently expressed in tumors with higher nuclear grade. The expression of CTAs has not been studied as extensively in ductal carcinoma in situ (DCIS) as it has been in invasive breast cancer. The present retrospective study included archived paraffin-embedded specimens from 83 patients diagnosed with DCIS in the period between January 2007 and December 2014. The follow-up time for local recurrence ranged between 1 and 8 years (mean, 5.02 years). Antigens from the melanoma-associated antigen gene (MAGE) family, namely multi-MAGE-A, MAGE-A1, MAGE-A10 and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) antigen, were evaluated by immunostaining and their subcellular location was investigated. Presence of tumor-infiltrating lymphocytes (TILs) was evaluated on all sections, together with the histopathological variables of DCIS. Specific tested antigens exhibited associations with histopathological parameters for DCIS and all demonstrated statistically significant associations with nuclear staining, simultaneous cytoplasmic and nuclear staining, and local recurrence. Antigen MAGE-A10 demonstrated a significant association with higher expression of ER (P=0.005) and higher tumor nuclear grade (P=0.001), cytoplasmic staining (P=0.029) and antigen NY-ESO-1 with higher tumor size (P=0.001), expression of TILs (P=0.001) and R1 resection (P=0.001). A χ2 test revealed significant associations between simultaneous cytoplasmic and nuclear staining and local recurrence (P=0.005), central necrosis (P=0.016), and the expression of ER (P=0.003) and progesterone receptor (PR) (P=0.010). Additional analysis revealed an association between antigen MAGE-A10 and TILs (P=0.05). Additional analysis of TILs indicated that they were significantly associated with tumor grade (P=0.023), central necrosis (P<0.001), ER (P=0.003) and PR (P=0.029). Overall, CTAs from the MAGE family (MAGE-A1, multi-MAGE-A and MAGE-A10) and NY-ESO-1 associate with histopathological predictive variables of DCIS. The expression of antigens NY-ESO-1 and MAGE-A10 could serve an important role in the treatment of patients with negative histopathological predictive variables, but further analysis is required. Simultaneous cytoplasmic and nuclear protein expression of MAGE-A family and NY-ESO-1 CTAs may represent an independent marker for local recurrence. Taken together, the present data suggest that CTAs are not perfect indicators of invasiveness for DCIS, but could inform treatment strategies for patients when taken in combination with other histopathological predictive variables. However, this was a small study and further larger studies will be necessary to confirm the cu...

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“…Like invasive breast carcinoma, some degree of lymphocytic infiltration is often present within or surrounding ducts involved by DCIS [87,88]. Pruneri et al have recently reported on the prevalence and clinical relevance of TILs in DCIS, in a large series with substantial length of follow up [88].…”

Section: Tils In Ductal Carcinoma In Situmentioning

confidence: 99%

Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method From the International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune Response, TILs in Invasive Breast Carcinoma and Ductal Carcinoma In Situ, Metastatic Tumor Deposits and Areas for Further Research

Hendry

Salgado

Gevaert

et al. 2017

Advances in Anatomic Pathology

520

374

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Assessment of tumor infiltrating lymphocytes (TILs) in histopathological specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible and reliable immuno-oncology biomarkers is clear. In Part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on H&E sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in Part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

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The prevalence and clinical relevance of tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ of the breast

Abstract: TILs occur more frequently in the Her-2 positive DCIS. Although we did not find a significant association between TILs and the 10-year risk of IBE, our data suggest that immunotherapies might be considered in subsets of DCIS patients.

Cited by 81 publications

References 21 publications

Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

Possible predictive role of cancer/testis antigens in breast ductal carcinoma in�situ

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