Skip to main content

Advertisement

SpringerLink
Log in

Podoplanin expression in cancer-associated fibroblasts predicts unfavorable prognosis in node-negative breast cancer patients with hormone receptor-positive/HER2 − negative subtype

  • Original Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Background

Podoplanin expression in cancer-associated fibroblasts (CAFs) has been proposed as an indicator for poor prognosis in patients with invasive breast carcinomas, but little is known about its clinical significance in node-negative breast cancer patients with hormone receptor (HR) + /HER2  − subtype, who are expected to have a favorable prognosis.

Methods

Immunohistochemical analyses were performed on 169 resected specimens of node-negative invasive carcinoma of no special type with HR + /HER2 − subtype using antibodies for podoplanin. When more than 10% of CAFs showed immunoreactivity with podoplanin as strong as that of internal positive controls, the specimens were judged as podoplanin-positive.

Results

Podoplanin-positive status in CAFs was observed in 16.0% (27 of 169 cases) and it associated with high Ki67 labeling index (LI) (> 30%) (p = 0.03), higher stromal tumor-infiltrating lymphocytes (p < 0.001) and progesterone receptor-negative status (p = 0.045). Log-rank test showed that podoplanin-positive status in CAFs correlated with shorter disease-free survival (DFS) (p = 0.007) and disease-specific survival (DSS) (p < 0.001). Univariate analysis showed a significant correlation between shorter DFS and podoplanin-positive status in CAFs (hazard ratio [HR] = 3.380; p = 0.012), the presence of lymphatic invasion (HR = 5.621; p < 0.001), high Ki67 LI (HR = 5.217; p < 0.001), and histological grade III (HR = 3.748; p = 0.008). According to Cox multivariate analysis, podoplanin-positive status in CAFs had the most significant effect on shorter DSS (HR = 37.759; p = 0.003) followed by high Ki67LI (HR = 27.664; p = 0.007).

Conclusion

Podoplanin expression in CAFs could be an independent predictor for poor prognosis in node-negative breast cancer patients with HR + /HER2 − subtype.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Global Burden of Disease Cancer Collaboration. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016. JAMA Oncol. 2018;1:1553–68. https://doi.org/10.1001/jamaoncol.2018.2706.

    Article  Google Scholar 

  2. Andersson Y, Bergkvist L, Frisell J, Boniface J. Long-term breast cancer survival in relation to the metastatic tumor burden in axillary lymph nodes. Breast Cancer Res Treat. 2018;171:359–69. https://doi.org/10.1007/s10549-018-4820-0.

    Article  PubMed  Google Scholar 

  3. Agostinetto E, Giordano L, Torrisi R, De Sanctis R, Masci G, Losurdo A, et al. Biological characteristics and long-term outcomes in node-negative breast cancer. Clin Breast Cancer. 2020. https://doi.org/10.1016/i.dbc.2020.02.011.

    Article  PubMed  Google Scholar 

  4. Arnaout-Alkarain A, Kahn HJ, Narod SA, Sun PA, Marks AN. Significance of lymph vessel invasion identified by the endothelial lymphatic marker D2–40 in node negative breast cancer. Mod Pathol. 2007;20:183–91. https://doi.org/10.1038/modpathol.3800728.

    Article  CAS  PubMed  Google Scholar 

  5. Waks AG, Winner EP. Breast cancer treatment: a review. JAMA. 2019;321:288–300. https://doi.org/10.1001/jama.2018.19323.

    Article  CAS  PubMed  Google Scholar 

  6. Parise CA, Caggiano V. Risk of mortality of node-negative, ER/PR/HER2 breast cancer subtypes in T1, T2 and T3 tumors. Breast Cancer Res Treat. 2017;165:743–50. https://doi.org/10.1007/s10549-017-4383-5.

    Article  PubMed  Google Scholar 

  7. Stemmer SM, Steiner M, Rizel S, Ben-Baruch N, Uziely B, Jakubowski DM, et al. Ten-year clinical outcomes in N0 ER+ breast cancer patients with recurrence score-guided therapy. NPJ Breast Cancer. 2019;5:41. https://doi.org/10.1038/s41523-019-0137-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ugorski M, Suchanski DP. Podoplanin-a small glycoprotein with many faces. Am J Cancer Res. 2016;6(2):370–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Houthuijzen JM, Jonkers J. Cancer-associated fibroblasts as key regulators of the breast cancer tumor microenvironment. Cancer Metastasis Rev. 2018;8(37):577–97. https://doi.org/10.1007/s10555-018-9768-3.

    Article  CAS  Google Scholar 

  10. Suchanski J, Tejchman A, Zacharski M, Piotrowska A, Grzegrzolka J, Nowinska K, et al. Podoplanin increases the migration of human fibroblasts and affects the endothelial cell network formation: a possible role for cancer-associated fibroblasts in breast cancer progression. PLoS ONE. 2017;12:e0184970. https://doi.org/10.1371/journal.pone.0184970.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yurugi Y, Wakahara M, Matsuoka Y, Sakabe T, Kubouchi Y, Haruki T, et al. Podoplanin expression in cancer-associated fibroblasts predicts poor prognosis in patients with squamous cells carcinoma of the lung. Anticancer Res. 2017;37:207–14.

    Article  CAS  PubMed  Google Scholar 

  12. Kubouchi Y, Yurugi Y, Wakahara M, Sakabe T, Haruki T, Nosaka K, et al. Podoplanin expression in cancer-associated fibroblasts predicts unfavourable prognosis in patients with pathological stage IA lung adenocarcinoma. Histopathol. 2018;72:490–9. https://doi.org/10.1111/his.13390.

    Article  Google Scholar 

  13. Maruyama S, Furuya S, Shiraishi K, Shimizu H, Akaike H, Kawaguchi Y, et al. Podoplanin expression as a prognostic factor in gastric cancer. Anticancer Res. 2018;38:2717–22.

    CAS  PubMed  Google Scholar 

  14. Schoppmann SF, Berghoff A, Dinhof C, Jakesz R, Gnant M, Dubsky P, et al. Podoplanin-expressing cancer-associated fibroblasts are associated with poor prognosis in invasive breast cancer. Breast Cancer Res Treat. 2012;134:237–44. https://doi.org/10.1007/s10549-012-1984-x.

    Article  CAS  PubMed  Google Scholar 

  15. Pula B, Jethom A, Piotrowska A, Gomulkiewicz A, Owczarek T, Calik J, et al. Podoplanin expression by cancer-associated fibroblasts predicts poor outcome in invasive ductal breast carcinoma. Histopathol. 2011;59:1249–60. https://doi.org/10.1111/j.1365-2559.2011.04060.x.

    Article  Google Scholar 

  16. WHO Classification of Tumours Editorial Board: Breast Tumours. WHO classification of tumours of the breast. Lyon: IARC; 2019.

    Google Scholar 

  17. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathol. 1991;19:403–10. https://doi.org/10.1111/j.1365-2559.1991.tb00229.x.

    Article  CAS  Google Scholar 

  18. James DB, Mary KG, Christian W. TNM classification of malignant tumours. 8th ed. UICC: Blackwell Publishing Ltd; 2017.

    Google Scholar 

  19. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an international TILs working group 2014. Annal Oncol. 2015;26:259–71. https://doi.org/10.1093/annonc/mdu450.

    Article  CAS  Google Scholar 

  20. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant chemotherapy guided a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379:111–21. https://doi.org/10.1056/NEJMoa1804710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018;19:40–50. https://doi.org/10.1016/S1470-2045(17)30904-X.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The Authors are grateful to Yuko Urakami and Kazuko Fukushima for their excellent technical assistance with the processing of the pathological specimens.

Author information

Authors and Affiliations

  1. Department of Pathology, Faculty of Medicine, Tottori University, 86 Nishicho, Yonago, Tottori, 683-8503, Japan

    Yuko Tanaka, Taichi Kadonaga, Kanae Nosaka, Tomohiko Sakabe & Yoshihisa Umekita

  2. Division of General Thoracic Surgery and Breast and Endocrine Surgery, Department of Surgery, Faculty of Medicine, Tottori University, Tottori, Japan

    Yuko Tanaka, Takashi Ohno, Taichi Kadonaga, Yoshiteru Kidokoro, Makoto Wakahara, Yoshimasa Suzuki & Hiroshige Nakamura

Authors
  1. Yuko Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takashi Ohno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taichi Kadonaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshiteru Kidokoro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Makoto Wakahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kanae Nosaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tomohiko Sakabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoshimasa Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiroshige Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoshihisa Umekita
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoshihisa Umekita.

Ethics declarations

Conflict of interest

The authors confirm that there are no conflicts of interest.

Ethical approval

This study was approved by the ethics committee of the Faculty of Medicine, Tottori University (approval number: 18A169; January 15, 2019).

Informed consent

As this study used only retrospective clinical data and offered no risk to the participants, written informed consent was not required.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tanaka, Y., Ohno, T., Kadonaga, T. et al. Podoplanin expression in cancer-associated fibroblasts predicts unfavorable prognosis in node-negative breast cancer patients with hormone receptor-positive/HER2 − negative subtype. Breast Cancer 28, 822–828 (2021). https://doi.org/10.1007/s12282-021-01217-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-021-01217-0

Keywords

Search

Navigation