Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2021

01-12-2021 | Breast Cancer | Review

Prognostic impact of tertiary lymphoid structures in breast cancer prognosis: a systematic review and meta-analysis

Authors: Na-Na Zhang, Feng-Jin Qu, Hao Liu, Zhu-Jun Li, Yu-Chi Zhang, Xuan Han, Zi-Yu Zhu, Yi Lv

Published in: Cancer Cell International | Issue 1/2021

Login to get access

Abstract

Background

Tertiary lymphoid structures (TLSs), organizationally resemble lymph nodes, are frequently present in breast cancer (BCa). It is usually, but not always, associated with a positive prognosis or immunotherapy response in cancer patients. This meta-analysis was performed to assess the prognostic and clinical impact of TLSs in BCa.

Methods

We conducted a systematic search in PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, and WanFang Database to obtain eligible research data up to May 30, 2021. This meta-analysis is focusing on the studies evaluated the prognostic value of TLSs and the associated clinicopathologic indicators, related gene expression and survival. STATA software 16.0 software was used to assess the prognostic significance and clinical impact of TLSs.

Results

Nine studies involved with 2281 cases were incorporated in this meta-analysis, in which four of them evaluated the prognostic value of TLSs. There are 6 studies assessed the relationship of TLSs and 4 studies investigated the clinicopathologic parameters as well as the key gene expression, respectively. The results showed the presence of TLSs were predicting a better OS (HR = 0.61, 95% CI: 0.51–0.73, p < 0.001) and DFS (HR = 0.40, 95% CI: 0.17–0.93, p < 0.001) of BCa patients. It also revealed that the presence of TLSs was significantly correlated with tumor differentiation (p < 0.001), pTNM stage (p < 0.001), lymph node metastasis (p < 0.001), and TILs density (p < 0.001) of BCa, and the expression of Her2 (p < 0.001), ER (p < 0.001), PR (p < 0.001) and Ki67 (p = 0.009) of the tumor cell.

Conclusion

Our results indicated that high levels of TLSs could predict a favorable prognosis for BCa. Moreover, the TLSs were significantly correlated with the clinicopathological indicators and the critical gene expression of BCa, indicating its potential clinical impact on BCa patients.
Appendix
Available only for authorised users
Literature
1.
DeSantis CE, Ma J, Gaudet MM, et al. Breast cancer statistics, 2019. CA A Cancer J Clin. 2019;69(6):438–51.CrossRef
2.
Greaney ML, Sprunck-Harrild K, Ruddy KJ, et al. Study protocol for Young & Strong: a cluster randomized design to increase attention to unique issues faced by young women with newly diagnosed breast cancer. BMC Public Health. 2015;15:37.PubMedPubMedCentralCrossRef
3.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA A Cancer J Clin. 2020;70(1):7–30.CrossRef
4.
5.
Heinhuis KM, Ros W, Kok M, et al. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors. Ann Oncol. 2019;30(2):219–35.PubMedCrossRef
6.
Adams S, Schmid P, Rugo HS, et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol. 2019;30(3):397–404.PubMedCrossRef
7.
Dirix LY, Takacs I, Jerusalem G, et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat. 2018;167(3):671–86.PubMedCrossRef
8.
Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34(21):2460–7.PubMedPubMedCentralCrossRef
9.
Adams S, Loi S, Toppmeyer D, et al. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann Oncol. 2019;30(3):405–11.PubMedCrossRef
10.
Sautes-Fridman C, Petitprez F, Calderaro J, et al. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019;19(6):307–25.PubMedCrossRef
11.
Colbeck EJ, Ager A, Gallimore A, et al. Tertiary lymphoid structures in cancer: drivers of antitumor immunity, immunosuppression, or bystander sentinels in disease? Front Immunol. 2017;8:1830.PubMedPubMedCentralCrossRef
12.
13.
Cabrita R, Lauss M, Sanna A, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020;577(7791):561–5.PubMedCrossRef
14.
Dieu-Nosjean MC, Giraldo NA, Kaplon H, Germain C, Fridman WH, Sautes-Fridman C. Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers. Immunol Rev. 2016;271(1):260–75.PubMedCrossRef
15.
Figenschau SL, Fismen S, Fenton KA, et al. Tertiary lymphoid structures are associated with higher tumor grade in primary operable breast cancer patients. BMC Cancer. 2015;15:101.PubMedPubMedCentralCrossRef
16.
Sofopoulos M, Fortis SP, Vaxevanis CK, et al. The prognostic significance of peritumoral tertiary lymphoid structures in breast cancer. Cancer Immunol Immunother. 2019;68(11):1733–45.PubMedCrossRef
17.
Kim A, Heo SH, Kim YA, et al. An examination of the local cellular immune response to examples of both ductal carcinoma in situ (dcis) of the breast and dcis with microinvasion, with emphasis on tertiary lymphoid structures and tumor infiltrating lymphoctytes. Am J Clin Pathol. 2016;146(1):137–44.PubMedCrossRef
18.
Zou Zhongwei. Expression of tertiary lymphoid structures in breast cancer and its clinical significance [Master dissertation]: University of South China. 2016.
19.
Lee HJ, Park IA, Song IH, et al. Tertiary lymphoid structures: prognostic significance and relationship with tumour-infiltrating lymphocytes in triple-negative breast cancer. J Clin Pathol. 2016;69(5):422–30.PubMedCrossRef
20.
Buisseret L, Garaud S, de Wind A, et al. Tumor-infiltrating lymphocyte composition, organization and PD-1/ PD-L1 expression are linked in breast cancer. Oncoimmunology. 2017;6(1):e1257452.PubMedCrossRef
21.
Gao Song. Expression and clinical significance of CD4 +, CD8 + lymphocytes and tertiary lymphoid structures in breast cancer tissues [Master dissertation]: University of South China. 2017.
22.
Liu X, Tsang J, Hlaing T, et al. Distinct tertiary lymphoid structure associations and their prognostic relevance in HER2 positive and negative breast cancers. Oncologist. 2017;22(11):1316–24.PubMedPubMedCentralCrossRef
23.
Lee M, Heo SH, Song IH, et al. Presence of tertiary lymphoid structures determines the level of tumor-infiltrating lymphocytes in primary breast cancer and metastasis. Mod Pathol. 2019;32(1):70–80.PubMedCrossRef
24.
25.
Bento DC, Jones E, Junaid S, et al. High endothelial venules are rare in colorectal cancers but accumulate in extra-tumoral areas with disease progression. Oncoimmunology. 2015;4(3):e974374.PubMedPubMedCentralCrossRef
26.
van Rijthoven M, Balkenhol M, Siliņa K, van der Laak J, Ciompi F. HookNet: Multi-resolution convolutional neural networks for semantic segmentation in histopathology whole-slide images. Med Image Anal. 2021;68:101890.PubMedCrossRef
27.
Bertucci F, Boudin L, Finetti P, et al. Immune landscape of inflammatory breast cancer suggests vulnerability to immune checkpoint inhibitors. Oncoimmunology. 2021;10(1):1929724.PubMedPubMedCentralCrossRef
28.
29.
30.
Wortman JC, He TF, Solomon S, et al. Spatial distribution of B cells and lymphocyte clusters as a predictor of triple-negative breast cancer outcome. NPJ Breast Cancer. 2021;7(1):84.PubMedPubMedCentralCrossRef
31.
Di Caro G, Bergomas F, Grizzi F, Doni A, Bianchi P, Malesci A, et al. Occurrence of tertiary lymphoid tissue is associated with T-cell infiltration and predicts better prognosis in early-stage colorectal cancers. Clin Cancer Res. 2014;20(8):2147–58.PubMedCrossRef
32.
Gennari R, Menard S, Fagnoni F, et al. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res. 2004;10(17):5650–5.PubMedCrossRef
33.
de Chaisemartin L, Goc J, Damotte D, et al. Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer. Cancer Res. 2011;71(20):6391–9.PubMedCrossRef
34.
Munoz-Erazo L, Rhodes JL, Marion VC, Kemp RA. Tertiary lymphoid structures in cancer—considerations for patient prognosis. Cell Mol Immunol. 2020;17(6):570–5.PubMedPubMedCentralCrossRef
35.
Denkert C, von Minckwitz G, Brase JC, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015;33(9):983–91.PubMedCrossRef
36.
Luen SJ, Salgado R, Fox S, et al. Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study. Lancet Oncol. 2017;18(1):52–62.PubMedCrossRef
37.
Kwon MJ. Emerging immune gene signatures as prognostic or predictive biomarkers in breast cancer. Arch Pharm Res. 2019;42(11):947–61.PubMedCrossRef
38.
Arab A, Yazdian-Robati R, Behravan J. HER2-positive breast cancer immunotherapy: a focus on vaccine development. Arch Immunol Ther Exp (Warsz). 2020;68(1):2.CrossRef
39.
Solinas C, Garaud S, De Silva P, et al. Immune checkpoint molecules on tumor-infiltrating lymphocytes and their association with tertiary lymphoid structures in human breast cancer. Front Immunol. 2017;8:1412.PubMedPubMedCentralCrossRef
40.
41.
Penault-Llorca F, Radosevic-Robin N. Ki67 assessment in breast cancer: an update. Pathology. 2017;49(2):166–71.PubMedCrossRef
42.
Yerushalmi R, Woods R, Ravdin PM, et al. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 2010;11(2):174–83.PubMedCrossRef
43.
Hiraoka N, Ino Y, Yamazaki-Itoh R, Kanai Y, Kosuge T, Shimada K. Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer. Br J Cancer. 2015;112(11):1782–90.PubMedPubMedCentralCrossRef
44.
Li H, Liu H, Fu H, et al. Peritumoral tertiary lymphoid structures correlate with protective immunity and improved prognosis in patients with hepatocellular carcinoma. Front Immunol. 2021;12:648812.PubMedPubMedCentralCrossRef
Metadata
Title
Prognostic impact of tertiary lymphoid structures in breast cancer prognosis: a systematic review and meta-analysis
Authors
Na-Na Zhang
Feng-Jin Qu
Hao Liu
Zhu-Jun Li
Yu-Chi Zhang
Xuan Han
Zi-Yu Zhu
Yi Lv
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-021-02242-x

Other articles of this Issue 1/2021

Cancer Cell International 1/2021 Go to the issue

Primary research

Decreased expression of METTL14 predicts poor prognosis and construction of a prognostic signature for clear cell renal cell carcinoma

Primary Research

CCR9 initiates epithelial–mesenchymal transition by activating Wnt/β-catenin pathways to promote osteosarcoma metastasis

Primary research

Development and validation of a risk prediction score for patients with nasopharyngeal carcinoma

Primary research

The immune‐related biomarker TEK inhibits the development of clear cell renal cell carcinoma (ccRCC) by regulating AKT phosphorylation

Review

Mitophagy in carcinogenesis, drug resistance and anticancer therapeutics

Primary research

VWCE as a potential biomarker associated with immune infiltrates in breast cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits