Abstract
Background
Growing evidence suggests that the tumor immune microenvironment influences breast cancer development and prognosis. Density of tumor-infiltrating lymphocytes (TILs) within invasive breast cancer is correlated with response to therapy, especially in triple-negative disease. The clinical relevance and outcomes of TILs within ductal carcinoma in situ (DCIS) are less understood.
Methods
Our institutional database of 668 patients with pure DCIS from 2010 to 2018 was queried. TILs were evaluated by International TILs Working Group guidelines. Percentage of TILs was assessed from the densest focus (hotspot) in one high-power field of stroma touching the basement membrane. Statistical methods included cluster analyses (to define sparse versus dense TILs), logistic, and Cox regression models.
Results
Sixty-nine patients with DCIS and TILs were evaluated, of whom 54 (78%) were treated by breast-conserving surgery. Thirteen (19%) patients had ipsilateral recurrence. Each recurrence (n = 13) was matched to four controls (n = 56) based on date of surgery. Median follow-up was 6.7 years. TILs were defined as sparse (< 45%) or dense (≥ 45%). Dense TILs were associated with younger age (p = 0.045), larger tumor size (p < 0.001), high nuclear grade (p = 0.010), comedo histology (p = 0.033), necrosis (p = 0.027), estrogen receptor (ER) negativity (p = 0.037), and ipsilateral recurrence (p = 0.001). Nine patients with dense TILs had mean time to recurrence of 73.5 months compared with four patients with sparse TILs with mean time to recurrence of 97.9 months (p = 0.003).
Conclusions
Dense TILs were significantly associated with age, tumor size, nuclear grade, comedo histology, necrosis, and ER status and was a significant predictor of recurrence in patients with pure DCIS.
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References
American Cancer Society. Breast cancer facts and figures 2017–2018. Atlanta: American Cancer Society, Inc.; 2017.
Pilewskie M, Olcese C, Patil S, Van Zee KJ. Women with low-risk DCIS eligible for the LORIS trial after complete surgical excision: how low is their risk after standard therapy? Ann Surg Oncol. 2016; 23(13):4253–61.
Shieh Y, Eklund M, Esserman L. Detection of ductal carcinoma in situ and subsequent interval cancers. BMJ 2016; 352:i551.
Ganz PA, Cecchini RS, Julian TB, et al. Patient-reported outcomes with anastrozole versus tamoxifen for postmenopausal patients with ductal carcinoma in situ treated with lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial. Lancet 2015; 387(10021):857–65.
Masood S. A call for change in the diagnosis and treatment of patients with ductal carcinoma in situ: an opportunity to minimize overdiagnosis and overtreatment. Breast J. 2015; 21:575–8.
Lippey J, Spillane A, Saunders C. Not all ductal carcinoma in situ is created equal: can we avoid surgery for low-risk ductal carcinoma in situ? ANZ J Surg. 2016; 86:859–60.
Benson JR, Jatoi I, Toi M. Treatment of low-risk ductal carcinoma in situ: is nothing better than something? Lancet Oncol. 2016; 17:e442–51.
Wahl RL. Quo vadis: PET and single-photon molecular breast imaging. J Nucl Med. 2016; 57(suppl 1):3S–8S.
Hoag H. Molecular biology: marked progress. Nature 2015; 527:S114–15.
Lari SA, Kuerer HM. Biological markers in DCIS and risk of breast recurrence: a systematic review. J Cancer 2011;2:232–61.
Narod SA, Iqbal J, Giannakeas V, Sopik V, Sun P. Breast cancer mortality after a diagnosis of ductal carcinoma in situ. JAMA Oncol. 2015;1:888–96.
Hughes LL, Wang M, Page DL, et al. Local excision alone without irradiation for ductal carcinoma in situ of the breast: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27:5319–24.
McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015; 33(7):709–15.
Carter CL, Allen C, Henson DE. Relation of tumour size, lymph node status, and survival in 24,740 breast cancer cases. Cancer 1989;63:181–7.
Narod SA. Age of diagnosis, tumor size, and survival after breast cancer: implications for mammographic screening. Breast Cancer Res Treat. 2011;128:259–66.
Kerlikowske K, Molinaro A, Cha I, et al. Characteristics associated with recurrence among women with ductal carcinoma in situ treated by lumpectomy. J Natl Cancer Inst. 2003;95(22):1692–702.
Foulkes WD, Reis-Filho JS, Narod SA. Tumor size and survival in breast cancer-a reappraisal. Nat Rev Clin Oncol. 2010;7(6):348–53.
Silverstein MJ. The University of Southern California/Van Nuys prognostic index for ductal carcinoma in situ of the breast. Am J Surg. 2003; 186(4):337–43.
Silverstein MJ, Lagios MD. Treatment selection for patients with ductal carcinoma in situ (DCIS) of the breast using the University of Southern California/Van Nuys (USC/VNPI) prognostic index. Breast J. 2015;21(2):127–32.
Mao Y, Qu Q, Chen X, Huang O, Wu J, Shen K. The prognostic value of tumor-infiltrating lymphocytes in breast cancer: a systematic review and meta-analysis. PLoS One 2016;11:e0152500.
Mohammed ZMA, Going JJ, Edwards J, Mcmillan DC. The role of the tumour inflammatory cell infiltrate in predicting recurrence and survival in patients with primary operable breast cancer. Cancer Treat Rev. 2012;38:943–55.
Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25(8):1544–50.
Adams S, Goldstein LJ, Sparano JA, Demaria S, Badve SS. Tumor infiltrating lymphocytes (TILs) improve prognosis in patients with triple negative breast cancer (TNBC). Oncoimmunology 2015;4:e985930.
Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31:860–7.
Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver, MJ. WHO classification of tumours of the breast. 4th ed. Lyon: International Agency for Research on Cancer; 2012.
Pruneri G, Lazzeroni M, Bagnardi V, Tiburzio GB, Rotmensz N et al. The prevalence and clinical relevance of tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ of the breast. Ann Oncol. 2017;28(2):321–8.
Hendry S, Salgado R, Gevaert T, Russell PA, John T, Thapa B, et al. 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. Adv Anat Pathol. 2017;24(5):235–51.
Silverstein MJ, Poller DN, Waisman JR, et al. Prognostic classification of breast ductal carcinoma-in-situ. Lancet 1995;345:1154–7.
Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991–8.
Beguinot M, Dauplat MM, Kwiatkowski F, Lebouedec G, Tixier L, Pomel C, et al. Analysis of tumour-infiltrating lymphocytes reveals two new biologically different subgroups of breast ductal carcinoma in situ. BMC Cancer 2018;18(1):129.
Semeraro M, Adam J, Stoll G, Louvet E, Chaba K, Poirier-Colame V, Sauvat A, Senovilla L, Vacchelli E, Bloy N, et al. The ratio of CD8+/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ. Oncoimmunology 2016;5:e1218106.
Coronella JA, Telleman P, Kingsbury GA, Truong TD, Hays S, Junghans RP. Evidence for an antigen-driven humoral immune response in medullary ductal breast cancer. Cancer Res. 2001;61:7889–99.
Ademuyiwa FO, Bshara W, Attwood K, Morrison C, Edge SB, et al. NY-ESO-1 cancer testis antigen demonstrates high immunogenicity in triple negative breast cancer. PLoS One 2012;7(6):e38783.
Agahozo MC, Hammerl D, Debets R, Kok M, van Deurzen CHM. Tumor-infiltrating lymphocytes and ductal carcinoma in situ of the breast: friends or foes? Mod Pathol. 2018;31:1012–25.
Thompson E, Taube JM, Elwood H, et al. The immune microenvironment of breast ductal carcinoma in situ. Mod Pathol. 2016;29:249–58.
Campbell MJ, Baehner F, O’Meara T, et al. Characterizing the immune microenvironment in high-risk ductal carcinoma in situ of the breast. Breast Cancer Res Treat. 2017;161:17–28.
Acknowledgment
We would like to acknowledge the Shifrin–Myers Breast Cancer Discovery Fund for funding this study.
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This article was presented at The American Society of Breast Surgeons 20th Annual Meeting in Dallas, TX; April 30–May 5, 2019.
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Darvishian, F., Ozerdem, U., Adams, S. et al. Tumor-Infiltrating Lymphocytes in a Contemporary Cohort of Women with Ductal Carcinoma In Situ (DCIS). Ann Surg Oncol 26, 3337–3343 (2019). https://doi.org/10.1245/s10434-019-07562-x
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DOI: https://doi.org/10.1245/s10434-019-07562-x