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Tumor-infiltrating lymphocyte abundance and programmed death-ligand 1 expression in metaplastic breast carcinoma: implications for distinct immune microenvironments in different metaplastic components

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Abstract

Both stromal tumor–infiltrating lymphocytes (sTILs) and programmed death-ligand 1 (PD-L1) affect responses to immunotherapy; however, the extent of sTIL and PD-L1 expression within various metaplastic components in metaplastic breast carcinoma (MBC), which are critical for the characterization of immune microenvironments, remains unreported. We profiled sTIL infiltration and PD-L1 expression in different metaplastic components of specimens from 82 MBC patients. The overall positivity for high or intermediate (H/I) sTIL, immune cell-PD-L1 (IcPD-L1), and tumor cell-PD-L1 (TcPD-L1) was 34.1%, 47.6%, and 17.1%, respectively, but differences specific to MBC subtypes and each metaplastic component existed. Squamous cell carcinoma exhibited the highest positivity rates of sTIL(H/I) (50.0%) and IcPD-L1 (66.7%), while matrix-producing carcinoma had the lowest respective rates (14.3% and 28.6%). The positivity rates of sTIL(H/I) and IcPD-L1 were the highest in squamous component (Sq) and the lowest in chondroid component (Ch). All cases that had discordant sTIL categories between carcinoma of no special type (NST) and metaplastic components showed sTIL(H/I) positivity higher in Sq, but lower in spindled component (Sp) and Ch. While there was no pattern of higher IcPD-L1-positivity in Sp, six of the seven cases that were TcPD-L1-discordant between NST and Sp were TcPD-L1-positive in Sp, suggesting a trend for higher TcPD-L1 in Sp. The diagnostic predictability of total tumor IcPD-L1 positivity based on IcPD-L1 positivity in Sq and Ch was 95.2% and 33.3%, respectively. Multivariate analysis showed that sTIL(H/I) positivity, but not PD-L1 positivity, correlated with better survival. Our data implicate distinct immune microenvironments in different metaplastic components in MBC, which may have immunopathologic, diagnostic, and therapeutic significance.

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References

  1. Pezzi CM, Patel-Parekh L, Cole K, Franko J, Klimberg VS, Bland K (2007) Characteristics and treatment of metaplastic breast cancer: analysis of 892 cases from the National Cancer Data Base. Ann Surg Oncol 14:166–173

    Article  Google Scholar 

  2. Aydiner A, Sen F, Tambas M, Ciftci R, Eralp Y, Saip P, Karanlik H, Fayda M, Kucucuk S, onder S, Yavuz E, Muslumanoglu M, Igci A (2015) Metaplastic breast carcinoma versus triple-negative breast cancer: survival and response to treatment. Medicine (Baltimore) 94:e2341

    Article  CAS  Google Scholar 

  3. Rayson D, Adjei AA, Suman VJ, Wold LE, Ingle JN (1999) Metaplastic breast cancer: prognosis and response to systemic therapy. Ann Oncol 10:413–419

    Article  CAS  Google Scholar 

  4. Stanton SE, Adams S, Disis ML (2016) Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes: a systematic review. JAMA Oncol 2:1354–1360

    Article  Google Scholar 

  5. Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, Budczies J, Huober J, Klauschen F, Furlanetto J, Schmitt WD, Blohmer JU, Karn T, Pfitzner BM, Kümmel S, Engels K, Schneeweiss A, Hartmann A, Noske A, Fasching PA, Jackisch C, van Mackelenbergh M, Sinn P, Schem C, Hanusch C, Untch M, Loibl S (2018) Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol 19:40–50

    Article  Google Scholar 

  6. Loibl S, Untch M, Burchardi N, Huober J, Sinn BV, Blohmer JU, Grischke EM, Furlanetto J, Tesch H, Hanusch C, Engels K, Rezai M, Jackisch C, Schmitt WD, von Minckwitz G, Thomalla J, Kümmel S, Rautenberg B, Fasching PA, Weber K, Rhiem K, Denkert C, Schneeweiss A (2019) A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann Oncol 30:1279–1288

    Article  CAS  Google Scholar 

  7. Gonzalez-Ericsson PI, Stovgaard ES, Sua LF, Reisenbichler E, Kos Z, Carter JM, Michiels S, le Quesne J, Nielsen TO, Lænkholm AV, Fox SB, Adam J, Bartlett JMS, Rimm DL, Quinn C, Peeters D, Dieci MV, Vincent-Salomon A, Cree I, Hida AI, Balko JM, Haynes HR, Frahm I, Acosta-Haab G, Balancin M, Bellolio E, Yang W, Kirtani P, Sugie T, Ehinger A, Castaneda CA, Kok M, McArthur H, Siziopikou K, Badve S, Fineberg S, Gown A, Viale G, Schnitt SJ, Pruneri G, Penault-Llorca F, Hewitt S, Thompson EA, Allison KH, Symmans WF, Bellizzi AM, Brogi E, Moore DA, Larsimont D, Dillon DA, Lazar A, Lien H, Goetz MP, Broeckx G, el Bairi K, Harbeck N, Cimino-Mathews A, Sotiriou C, Adams S, Liu SW, Loibl S, Chen IC, Lakhani SR, Juco JW, Denkert C, Blackley EF, Demaria S, Leon-Ferre R, Gluz O, Zardavas D, Emancipator K, Ely S, Loi S, Salgado R, Sanders M, International Immuno‐Oncology Biomarker Working Group (2020) The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers into breast cancer clinical trials and daily practice. J Pathol 250:667–684

    Article  CAS  Google Scholar 

  8. Schmid P, Chui SY, Emens LA (2019) Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. Reply. N Engl J Med 380:987–988

    PubMed  Google Scholar 

  9. Joneja U, Vranic S, Swensen J, Feldman R, Chen W, Kimbrough J, Xiao N, Reddy S, Palazzo J, Gatalica Z (2017) Comprehensive profiling of metaplastic breast carcinomas reveals frequent overexpression of programmed death-ligand 1. J Clin Pathol 70:255–259

    Article  CAS  Google Scholar 

  10. Gonzalez-Martinez S, Perez-Mies B, Carretero-Barrio I, Palacios-Berraquero ML, Perez-Garcia J, Cortes J, Palacios J (2020) Molecular features of metaplastic breast carcinoma: an infrequent subtype of triple negative breast carcinoma. Cancers (Basel):12(7)

  11. Tray N, Taff J, Singh B, Suh J, Ngo N, Kwa M, Troxel AB, Chae YK, Kurzrock R, Patel SP, Sharon E, Denkert C, Ross JS, Adams S (2019) Metaplastic breast cancers: genomic profiling, mutational burden and tumor-infiltrating lymphocytes. Breast 44:29–32

    Article  Google Scholar 

  12. Alsuliman A, Colak D, Al-Harazi O, Fitwi H, Tulbah A, Al-Tweigeri T, Al-Alwan M, Ghebeh H (2015) Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells. Mol Cancer 14:149

    Article  Google Scholar 

  13. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, Wienert S, van den Eynden G, Baehner FL, Penault-Llorca F, Perez EA, Thompson EA, Symmans WF, Richardson AL, Brock J, Criscitiello C, Bailey H, Ignatiadis M, Floris G, Sparano J, Kos Z, Nielsen T, Rimm DL, Allison KH, Reis-Filho JS, Loibl S, Sotiriou C, Viale G, Badve S, Adams S, Willard-Gallo K, Loi S, International TILs Working Group 2014 (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26:259–271

    Article  CAS  Google Scholar 

  14. Dill EA, Gru AA, Atkins KA, Friedman LA, Moore ME, Bullock TN, Cross JV, Dillon PM, Mills AM (2017) PD-L1 expression and Intratumoral heterogeneity across breast cancer subtypes and stages: an assessment of 245 primary and 40 metastatic tumors. Am J Surg Pathol 41:334–342

    Article  Google Scholar 

  15. Afkhami M, Schmolze D, Yost SE, Frankel PH, Dagis A, Amanam IU, Telatar M, Nguyen K, Yu KW, Luu T, Pillai R, Aoun PA, Mortimer J, Yuan Y (2019) Mutation and immune profiling of metaplastic breast cancer: correlation with survival. PLoS One 14:e0224726

    Article  CAS  Google Scholar 

  16. Chao X, Liu L, Sun P, Yang X, Li M, Luo R, Huang Y, He J, Yun J (2020) Immune parameters associated with survival in metaplastic breast cancer. Breast Cancer Res 22:92

    Article  CAS  Google Scholar 

  17. Kalaw E, Lim M, Kutasovic JR, Sokolova A, Taege L, Johnstone K, Bennett J, Saunus JM, Niland C, Ferguson K, Gresshoff I, Bettington M, Pathmanathan N, Tse GM, Papadimos D, Pathmanathan R, Harris G, Yamaguchi R, Tan PH, Fox S, O’Toole SA, Simpson PT, Lakhani SR, McCart Reed AE (2020) Metaplastic breast cancers frequently express immune checkpoint markers FOXP3 and PD-L1. Br J Cancer. https://doi.org/10.1038/s41416-020-01065-3

  18. Hendry S, Salgado R, Gevaert T et al (2017) Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors. Adv Anat Pathol 24:311–335

    Article  Google Scholar 

  19. Adams S, Othus M, Patel SP et al (2020) Dual anti-CTLA-4 and anti-PD-1 blockade in metaplastic carcinoma of the breast: Dart (SWOG S1609, Cohort

  20. Allison KHBE, Ellis IO, Fox SB, Lakhani SR, Lax SF, Sahin A, Salgado R, Sapino A, Sasano H, Schnitt SJ, Tan PH, Thompson LDR, van Diest PJ (2019) Epithelial tumours of the breast. In: WHO Classification of Tumours Breast Tumours, 5th edn. IRAC, Lyon, p 136

    Google Scholar 

  21. Krings G, Chen YY (2018) Genomic profiling of metaplastic breast carcinomas reveals genetic heterogeneity and relationship to ductal carcinoma. Mod Pathol 31:1661–1674

    Article  CAS  Google Scholar 

  22. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454

    Article  CAS  Google Scholar 

  23. Kawakami F, Sircar K, Rodriguez-Canales J, Fellman BM, Urbauer DL, Tamboli P, Tannir NM, Jonasch E, Wistuba II, Wood CG, Karam JA (2017) Programmed cell death ligand 1 and tumor-infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation. Cancer 123:4823–4831

    Article  CAS  Google Scholar 

  24. Kim S, Kim MY, Koh J, Go H, Lee DS, Jeon YK, Chung DH (2015) Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: comparison of sarcomatous and carcinomatous areas. Eur J Cancer 51:2698–2707

    Article  CAS  Google Scholar 

  25. Vranic S, Stafford P, Palazzo J, Skenderi F, Swensen J, Xiu J, Spetzler D, Gatalica Z (2020) Molecular profiling of the metaplastic spindle cell carcinoma of the breast reveals potentially targetable biomarkers. Clin Breast Cancer 20(326–331):e321

    Google Scholar 

  26. Loi S, Drubay D, Adams S, Pruneri G, Francis PA, Lacroix-Triki M, Joensuu H, Dieci MV, Badve S, Demaria S, Gray R, Munzone E, Lemonnier J, Sotiriou C, Piccart MJ, Kellokumpu-Lehtinen PL, Vingiani A, Gray K, Andre F, Denkert C, Salgado R, Michiels S (2019) Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers. J Clin Oncol 37:559–569

    Article  Google Scholar 

  27. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S, Wang M, Jones VE, Saphner TJ, Wolff AC, Wood WC, Davidson NE, Sledge GW, Sparano JA, Badve SS (2014) Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 32:2959–2966

    Article  Google Scholar 

  28. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, van Eenoo F, Rouas G, Francis P, Crown JPA, Hitre E, de Azambuja E, Quinaux E, di Leo A, Michiels S, Piccart MJ, Sotiriou C (2013) 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 31:860–867

    Article  CAS  Google Scholar 

  29. Mori H, Kubo M, Yamaguchi R, Nishimura R, Osako T, Arima N, Okumura Y, Okido M, Yamada M, Kai M, Kishimoto J, Oda Y, Nakamura M (2017) The combination of PD-L1 expression and decreased tumor-infiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer. Oncotarget 8:15584–15592

    Article  Google Scholar 

  30. Tomioka N, Azuma M, Ikarashi M, Yamamoto M, Sato M, Watanabe KI, Yamashiro K, Takahashi M (2018) The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC). Breast Cancer 25:34–42

    Article  Google Scholar 

  31. Chen IC, Lin CH, Huang CS, Lien HC, Hsu C, Kuo WH, Lu YS, Cheng AL (2011) Lack of efficacy to systemic chemotherapy for treatment of metaplastic carcinoma of the breast in the modern era. Breast Cancer Res Treat 130:345–351

    Article  CAS  Google Scholar 

  32. Adams S (2017) Dramatic response of metaplastic breast cancer to chemo-immunotherapy. NPJ Breast Cancer 3:8

    Article  Google Scholar 

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Funding

This study was funded by the National Science Council Grant NSC 108-2320-B-002-061.

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Authors and Affiliations

  1. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

    Huang-Chun Lien, Yi-Hsuang Lee & Yueh-Tong Lu

  2. Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan

    Huang-Chun Lien

  3. Department of Oncology, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei, 10016, Taiwan

    I-Chun Chen, Ching-Hung Lin, Tom Wei-Wu Chen & Yen-Shen Lu

  4. Department of Medical Oncology, National Taiwan University Cancer Center Hospital, Taipei, Taiwan

    I-Chun Chen & Ching-Hung Lin

  5. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Ching-Hung Lin & Yen-Shen Lu

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Contributions

HCL and YSL: conception and design of the work, analysis and interpretation of data, and drafting the manuscript. HCL, YHL, and YTL: interpretation of sections. ICC, CHL, TWWC, and YSL: collection and evaluation of clinical data. HCL, YHL, ICC, CHL, TWWC, YTL, and YSL read, edited, and approved the final manuscript.

Corresponding author

Correspondence to Yen-Shen Lu.

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This study was approved by the institutional review board of the National Taiwan University Hospital (202004007RIN). Samples were used in accordance with ethical guidelines for the use of retrospective tissue samples provided by the institutional review board of the National Taiwan University Hospital.

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The authors declare that they have no competing interests.

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Lien, HC., Lee, YH., Chen, IC. et al. Tumor-infiltrating lymphocyte abundance and programmed death-ligand 1 expression in metaplastic breast carcinoma: implications for distinct immune microenvironments in different metaplastic components. Virchows Arch 478, 669–678 (2021). https://doi.org/10.1007/s00428-020-02954-x

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  • DOI: https://doi.org/10.1007/s00428-020-02954-x

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