Macrophage Density is an Adverse Prognosticator for Ipsilateral Recurrence in Ductal Carcinoma in Situ

Overview

Journal Breast

Publisher Elsevier

Specialties Endocrinology
Oncology

Date 2022 Apr 30

PMID 35489232

Authors

Farbod Darvishian

Yinxiang Wu

Ugur Ozerdem

Jennifer Chun

Sylvia Adams

Amber Guth

Deborah Axelrod

Richard Shapiro

Andrea B Troxel

Freya Schnabel

Daniel Roses

Affiliations

Soon will be listed here.

Abstract

Introduction: There is evidence that supports the association of dense tumor infiltrating lymphocyte (TILs) with an increased risk of ipsilateral recurrence in ductal carcinoma in situ (DCIS). However, the association of cellular composition of DCIS immune microenvironment with the histopathologic parameters and outcome is not well understood.

Methods: We queried our institutional database for patients with pure DCIS diagnosed between 2010 and 2019. Immunohistochemical studies for CD8, CD4, CD68, CD163, and FOXP3 were performed and evaluated in the DCIS microenvironment using tissue microarrays. Statistical methods included Fisher's exact test for categorical variables and the two-sample t-test or the Wilcoxon Rank-Sum test for continuous variables.

Results: The analytic sample included 67 patients. Median age was 62 years (range = 53 to 66) and median follow up was 6.7 years (range = 5.3 to 7.8). Thirteen patients had ipsilateral recurrence. Of all the clinicopathologic variables, only the DCIS size and TIL density were significantly associated with recurrence (p = 0.023 and 0.006, respectively). After adjusting for age and TIL density, only high CD68 (>50) and high CD68/CD163 ratio (>0.46) correlated with ipsilateral recurrence (p = 0.026 and 0.013, respectively) and shorter time to recurrence [hazard ratio 4.87 (95% CI: 1.24-19, p = 0.023) and 10.32 (95% CI: 1.34-80, p = 0.025), respectively].

Conclusions: In addition to DCIS size and TIL density, high CD68 tumor-associated macrophages predict ipsilateral recurrence in DCIS. High CD68 macrophage density and CD68/CD163 ratio also predict a shorter time to recurrence.

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References

Semeraro M, Adam J, Stoll G, Louvet E, Chaba K, Poirier-Colame V . The ratio of CD8/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma . Oncoimmunology. 2016; 5(10):e1218106. PMC: 5087306. DOI: 10.1080/2162402X.2016.1218106. View

Schreiber R, Old L, Smyth M . Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011; 331(6024):1565-70. DOI: 10.1126/science.1203486. View

Chanmee T, Ontong P, Konno K, Itano N . Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel). 2014; 6(3):1670-90. PMC: 4190561. DOI: 10.3390/cancers6031670. View

Dunn G, Bruce A, Ikeda H, Old L, Schreiber R . Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002; 3(11):991-8. DOI: 10.1038/ni1102-991. View

Bates G, Fox S, Han C, Leek R, Garcia J, Harris A . Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006; 24(34):5373-80. DOI: 10.1200/JCO.2006.05.9584. View

Gordon S . Alternative activation of macrophages. Nat Rev Immunol. 2003; 3(1):23-35. DOI: 10.1038/nri978. View

Mahmoud S, Lee A, Paish E, Macmillan R, Ellis I, Green A . Tumour-infiltrating macrophages and clinical outcome in breast cancer. J Clin Pathol. 2011; 65(2):159-63. DOI: 10.1136/jclinpath-2011-200355. View

Alkhateeb A, Han B, Connor J . Ferritin stimulates breast cancer cells through an iron-independent mechanism and is localized within tumor-associated macrophages. Breast Cancer Res Treat. 2013; 137(3):733-44. DOI: 10.1007/s10549-012-2405-x. View

Mahmoud S, Paish E, Powe D, Macmillan R, Grainge M, Lee A . Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011; 29(15):1949-55. DOI: 10.1200/JCO.2010.30.5037. View

10.

Hammond M, Hayes D, Wolff A, Mangu P, Temin S . American society of clinical oncology/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Oncol Pract. 2010; 6(4):195-7. PMC: 2900870. DOI: 10.1200/JOP.777003. View

11.

Agahozo M, Hammerl D, Debets R, Kok M, van Deurzen C . Tumor-infiltrating lymphocytes and ductal carcinoma in situ of the breast: friends or foes?. Mod Pathol. 2018; 31(7):1012-1025. DOI: 10.1038/s41379-018-0030-x. View

12.

Morita M, Yamaguchi R, Tanaka M, Tse G, Yamaguchi M, Kanomata N . CD8(+) tumor-infiltrating lymphocytes contribute to spontaneous "healing" in HER2-positive ductal carcinoma in situ. Cancer Med. 2016; 5(7):1607-18. PMC: 4944888. DOI: 10.1002/cam4.715. View

13.

Ali H, Provenzano E, Dawson S, Blows F, Liu B, Shah M . Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol. 2014; 25(8):1536-43. DOI: 10.1093/annonc/mdu191. View

14.

Sharma M, Beck A, Webster J, Espinosa I, Montgomery K, Varma S . Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ. Breast Cancer Res Treat. 2009; 123(2):397-404. PMC: 2976659. DOI: 10.1007/s10549-009-0654-0. View

15.

Wolff A, Hammond M, Allison K, Harvey B, Mangu P, Bartlett J . Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol. 2018; 36(20):2105-2122. DOI: 10.1200/JCO.2018.77.8738. View

16.

Medrek C, Ponten F, Jirstrom K, Leandersson K . The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer. 2012; 12:306. PMC: 3414782. DOI: 10.1186/1471-2407-12-306. View

17.

Campbell M, Baehner F, OMeara T, Ojukwu E, Han B, Mukhtar R . Characterizing the immune microenvironment in high-risk ductal carcinoma in situ of the breast. Breast Cancer Res Treat. 2016; 161(1):17-28. PMC: 5225037. DOI: 10.1007/s10549-016-4036-0. View

18.

Chen X, Thike A, Nasir N, Koh V, Bay B, Tan P . Higher density of stromal M2 macrophages in breast ductal carcinoma in situ predicts recurrence. Virchows Arch. 2020; 476(6):825-833. DOI: 10.1007/s00428-019-02735-1. View

19.

Pruneri G, Lazzeroni M, Bagnardi V, Tiburzio G, Rotmensz N, DeCensi A . The prevalence and clinical relevance of tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ of the breast. Ann Oncol. 2017; 28(2):321-328. DOI: 10.1093/annonc/mdw623. View

20.

Pollard J . Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004; 4(1):71-8. DOI: 10.1038/nrc1256. View