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

Abstract

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.

Targeting PARP1 in XRCC1-Deficient Sporadic Invasive Breast Cancer or Preinvasive Ductal Carcinoma In Situ Induces Synthetic Lethality and Chemoprevention

“…Importantly, PD-1 þ or PD-L1 þ breast cancers with low XRCC1 were linked to aggressive cancers and reduced survival including in ERbreast cancers (13). As immune microenvironment (including PD-L1 þ TILs infiltration) in DCIS can influence aggressive phenotypes (28,29), we propose that PARP1 targeting may be a promising personalized approach either alone or in combination with immune checkpoint inhibitors in XRCC1deficient invasive cancers and in preinvasive DCIS.…”

Alterations in Immune-Related Genes as Potential Marker of Prognosis in Breast Cancer

“…Recent studies have demonstrated that different pathological breast cancer subtypes have different genetic characteristics. TP53 and PIK3CA mutations are common in ductal breast carcinoma (18,19), while mucinous carcinoma lacks PIK3CA mutation (20). ERBB2 mutation is commonly present in both infiltrating lobular carcinoma and mucinous carcinoma (21,22).…”

Differential Expression of Cancer-Associated Fibroblast-Related Proteins in Ductal Carcinoma in situ According to Molecular Subtype and Stromal Histology

“…It has been reported that actin cytoskeleton signaling is associated with NG2 [29] and PDGFR [30], while integrin signaling is associated with S100A4 [31][32][33] and NG2 [34][35][36]. It has also been reported that molecular features that induce disease progression are different in each intrinsic molecular subtype of DCIS [24] and have an important role in the tumor microenvironment and progression of DCIS [37,38]. CAF-related proteins also have an intrinsic function.…”