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The prognostic significance of B lymphocytes in invasive carcinoma of the breast

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Abstract

Although the favourable role of T lymphocyte populations in different tumour types is established, that of B cells is still a matter of debate and needs further clarification. The presence of tumour-infiltrating B cells may represent an antibody response against breast tumour antigens. We used immunohistochemistry to investigate the density and localisation of B lymphocytes infiltrating 1470 breast tumours and to identify any prognostic significance and relationship to various clinicopathological factors. Higher numbers of CD20+ cells were found in the stroma away from the carcinoma (mean 12 cells) compared with either intratumoural or adjacent stromal compartments (mean 1 cell). The majority of tumours showed a diffuse pattern of B cells rather than aggregates. There was a positive correlation between higher numbers of total CD20+ B cells and higher tumour grade (r s = 0.20, P < 0.001), ER and PgR negativity (P < 0.001), and basal phenotype (P < 0.001) subclass. In univariate survival analysis, higher total number of infiltrating CD20+ cells, irrespective of location, was associated with significantly better BCSS (P = 0.037) and longer DFI (P = 0.001). In multivariate analysis, total CD20+ B cell count (HR = 0.75, 95% CI = 0.58–0.96 for BCSS and HR = 0.72, 95% CI = 0.58–0.89, for DFI), tumour size, nodal stage, grade, vascular invasion, HER-2 status, and total CD8+ T cell count were independently associated with outcome. This suggests that humoral immunity, in addition to the cell mediated immunity, may be important in breast cancer. This should be considered in breast cancer immunotherapy and vaccine strategies.

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References

  1. Bouaziz JD, Yanaba K, Venturi GM, Wang Y, Tisch RM, Poe JC et al (2007) Therapeutic B cell depletion impairs adaptive and autoreactive CD4+ T cell activation in mice. Proc Natl Acad Sci USA 104(52):20878–20883

    Article  PubMed  CAS  Google Scholar 

  2. Crawford A, Macleod M, Schumacher T, Corlett L, Gray D (2006) Primary T cell expansion and differentiation in vivo requires antigen presentation by B cells. J Immunol 176(6):3498–3506

    PubMed  CAS  Google Scholar 

  3. Coughlin CM, Vance BA, Grupp SA, Vonderheide RH (2004) RNA-transfected CD40-activated B cells induce functional T-cell responses against viral and tumor antigen targets: implications for pediatric immunotherapy. Blood 103(6):2046–2054

    Article  PubMed  CAS  Google Scholar 

  4. Schultz KR, Klarnet JP, Gieni RS, HayGlass KT, Greenberg PD (1990) The role of B cells for in vivo T cell responses to a Friend virus-induced leukemia. Science 249(4971):921–923

    Article  PubMed  CAS  Google Scholar 

  5. de Visser KE, Korets LV, Coussens LM (2005) De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7(5):411–423

    Article  PubMed  Google Scholar 

  6. Houghton AN, Uchi H, Wolchok JD (2005) The role of the immune system in early epithelial carcinogenesis: B-ware the double-edged sword. Cancer Cell 7(5):403–405

    Article  PubMed  CAS  Google Scholar 

  7. Bernatsky S, Ramsey-Goldman R, Clarke A (2006) Malignancy and autoimmunity. Curr Opin Rheumatol 18(2):129–134

    Article  PubMed  Google Scholar 

  8. Tomer Y, Sherer Y, Shoenfeld Y (1998) Autoantibodies, autoimmunity and cancer (review). Oncol Rep 5(3):753–761

    PubMed  CAS  Google Scholar 

  9. Milne K, Kobel M, Kalloger SE, Barnes RO, Gao D, Gilks CB et al (2009) Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors. PLoS One 4(7):e6412

    Article  PubMed  Google Scholar 

  10. Dong HP, Elstrand MB, Holth A, Silins I, Berner A, Trope CG et al (2006) NK- and B-cell infiltration correlates with worse outcome in metastatic ovarian carcinoma. Am J Clin Pathol 125(3):451–458

    PubMed  Google Scholar 

  11. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT (2008) Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res 14(16):5220–5227

    Article  PubMed  CAS  Google Scholar 

  12. Kuroda H, Tamaru J, Sakamoto G, Ohnisi K, Itoyama S (2005) Immunophenotype of lymphocytic infiltration in medullary carcinoma of the breast. Virchows Arch 446(1):10–14

    Article  PubMed  Google Scholar 

  13. Hansen MH, Nielsen HV, Ditzel HJ (2002) Translocation of an intracellular antigen to the surface of medullary breast cancer cells early in apoptosis allows for an antigen-driven antibody response elicited by tumor-infiltrating B cells. J Immunol 169(5):2701–2711

    PubMed  CAS  Google Scholar 

  14. Hansen MH, Nielsen H, Ditzel HJ (2001) The tumor-infiltrating B cell response in medullary breast cancer is oligoclonal and directed against the autoantigen actin exposed on the surface of apoptotic cancer cells. Proc Natl Acad Sci USA 98(22):12659–12664

    Article  PubMed  CAS  Google Scholar 

  15. Lee AH, Happerfield LC, Bobrow LG, Millis RR (1997) Angiogenesis and inflammation in invasive carcinoma of the breast. J Clin Pathol 50(8):669–673

    Article  PubMed  CAS  Google Scholar 

  16. Nzula S, Going JJ, Stott DI (2003) Antigen-driven clonal proliferation, somatic hypermutation, and selection of B lymphocytes infiltrating human ductal breast carcinomas. Cancer Res 63(12):3275–3280

    PubMed  CAS  Google Scholar 

  17. Coronella JA, Spier C, Welch M, Trevor KT, Stopeck AT, Villar H et al (2002) Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast. J Immunol 169(4):1829–1836

    PubMed  CAS  Google Scholar 

  18. Lee AH, Happerfield LC, Millis RR, Bobrow LG (1996) Inflammatory infiltrate in invasive lobular and ductal carcinoma of the breast. Br J Cancer 74(5):796–801

    Article  PubMed  CAS  Google Scholar 

  19. Tedder TF, Engel P (1994) CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol Today 15(9):450–454

    Article  PubMed  CAS  Google Scholar 

  20. Stashenko P, Nadler LM, Hardy R, Schlossman SF (1980) Characterization of a human B lymphocyte-specific antigen. J Immunol 125(4):1678–1685

    PubMed  CAS  Google Scholar 

  21. Cragg MS, Walshe CA, Ivanov AO, Glennie MJ (2005) The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun 8:140–174

    Article  PubMed  CAS  Google Scholar 

  22. Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JF et al (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116(3):340–350

    Article  PubMed  CAS  Google Scholar 

  23. Rakha EA, Putti TC, Abd El-Rehim DM, Paish C, Green AR, Powe DG et al (2006) Morphological and immunophenotypic analysis of breast carcinomas with basal and myoepithelial differentiation. J Pathol 208(4):495–506

    Article  PubMed  CAS  Google Scholar 

  24. Elston CW, Ellis IO (1991) 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. Histopathology 19(5):403–410

    Article  PubMed  CAS  Google Scholar 

  25. Ellis IO, Galea M, Broughton N, Locker A, Blamey RW, Elston CW (1992) Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up. Histopathology 20(6):479–489

    Article  PubMed  CAS  Google Scholar 

  26. Galea MH, Blamey RW, Elston CE, Ellis IO (1992) The Nottingham Prognostic Index in primary breast cancer. Breast Cancer Res Treat 22(3):207–219

    Article  PubMed  CAS  Google Scholar 

  27. Pinder SE, Ellis IO, Galea M, O’Rouke S, Blamey RW, Elston CW (1994) Pathological prognostic factors in breast cancer. III. Vascular invasion: relationship with recurrence and survival in a large study with long-term follow-up. Histopathology 24(1):41–47

    Article  PubMed  CAS  Google Scholar 

  28. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23(36):9067–9072

    Article  PubMed  Google Scholar 

  29. Camp RL, Charette LA, Rimm DL (2000) Validation of tissue microarray technology in breast carcinoma. Lab Invest 80(12):1943–1949

    Article  PubMed  CAS  Google Scholar 

  30. Mahmoud SMA, Paish EC, Powe DG, Macmillan RD, Lee AHS, Ellis IO et al (2011) An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer. Breast Cancer Res Treat 127(1):99–108

    Google Scholar 

  31. Rakha EA, El-Sheikh SE, Kandil MA, El-Sayed ME, Green AR, Ellis IO (2008) Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum Pathol 39(6):857–865

    Article  PubMed  CAS  Google Scholar 

  32. Mahmoud SMA, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AHS et al (2011) Tumor-infiltarting CD8+ lymphocytes predicts clinical outcome in breast cancer. J Clin Oncol 29(15):1949-1955

    Google Scholar 

  33. Cox DR (1972) Regression models and life-tables. J R Stat Soc Series B Stat Methodol 34(2):187–220

    Google Scholar 

  34. Camp RL, Dolled-Filhart M, Rimm DL (2004) X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10(21):7252–7259

    Article  PubMed  CAS  Google Scholar 

  35. Dolled-Filhart M, McCabe A, Giltnane J, Cregger M, Camp RL, Rimm DL (2006) Quantitative in situ analysis of beta-catenin expression in breast cancer shows decreased expression is associated with poor outcome. Cancer Res 66(10):5487–5494

    Article  PubMed  CAS  Google Scholar 

  36. Abd El-Rehim DM, Pinder SE, Paish CE, Bell J, Blamey RW, Robertson JF et al (2004) Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol 203(2):661–671

    Article  PubMed  Google Scholar 

  37. Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO (2007) Prognostic markers in triple-negative breast cancer. Cancer 109(1):25–32

    Article  PubMed  CAS  Google Scholar 

  38. Rakha EA, El-Rehim DA, Paish C, Green AR, Lee AH, Robertson JF et al (2006) Basal phenotype identifies a poor prognostic subgroup of breast cancer of clinical importance. Eur J Cancer 42(18):3149–3156

    Article  PubMed  CAS  Google Scholar 

  39. Marsigliante S, Biscozzo L, Marra A, Nicolardi G, Leo G, Lobreglio GB et al (1999) Computerised counting of tumour infiltrating lymphocytes in 90 breast cancer specimens. Cancer Lett 139(1):33–41

    Article  PubMed  CAS  Google Scholar 

  40. Naukkarinen A, Syrjanen KJ (1990) Quantitative immunohistochemical analysis of mononuclear infiltrates in breast carcinomas—correlation with tumour differentiation. J Pathol 160(3):217–222

    Article  PubMed  CAS  Google Scholar 

  41. Stewart TH, Heppner GH (1997) Immunological enhancement of breast cancer. Parasitology 115(Suppl):S141–S153

    Article  PubMed  Google Scholar 

  42. Rohrer JW, Barsoum AL, Dyess DL, Tucker JA, Coggin JH Jr (1999) Human breast carcinoma patients develop clonable oncofetal antigen-specific effector and regulatory T lymphocytes. J Immunol 162(11):6880–6892

    PubMed  CAS  Google Scholar 

  43. Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL et al (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24(34):5373–5380

    Article  PubMed  Google Scholar 

  44. Bilik R, Mor C, Hazaz B, Moroz C (1989) Characterization of T-lymphocyte subpopulations infiltrating primary breast cancer. Cancer Immunol Immunother 28(2):143–147

    Article  PubMed  CAS  Google Scholar 

  45. Georgiannos SN, Renaut A, Goode AW, Sheaff M (2003) The immunophenotype and activation status of the lymphocytic infiltrate in human breast cancers, the role of the major histocompatibility complex in cell-mediated immune mechanisms, and their association with prognostic indicators. Surgery 134(5):827–834

    Article  PubMed  Google Scholar 

  46. Aaltomaa S, Lipponen P, Eskelinen M, Kosma VM, Marin S, Alhava E et al (1992) Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur J Cancer 28A(4–5):859–864

    Article  PubMed  CAS  Google Scholar 

  47. Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H et al (2008) The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res 68(13):5405–5413

    Article  PubMed  CAS  Google Scholar 

  48. Lee AH, Gillett CE, Ryder K, Fentiman IS, Miles DW, Millis RR (2006) Different patterns of inflammation and prognosis in invasive carcinoma of the breast. Histopathology 48(6):692–701

    Article  PubMed  CAS  Google Scholar 

  49. Lee AHS (2008) Inflammation and vascularity in carcinoma of the breast. University of Cambridge, Cambridge

    Google Scholar 

  50. Balch CM, Riley LB, Bae YJ, Salmeron MA, Platsoucas CD, von Eschenbach A et al (1990) Patterns of human tumor-infiltrating lymphocytes in 120 human cancers. Arch Surg 125(2):200–205

    Article  PubMed  CAS  Google Scholar 

  51. Lee YT, Sheikh KM, Quismorio FP Jr, Friou GJ (1985) Circulating anti-tumor and autoantibodies in breast carcinoma: relationship to stage and prognosis. Breast Cancer Res Treat 6(1):57–65

    Article  PubMed  CAS  Google Scholar 

  52. Coronella-Wood JA, Hersh EM (2003) Naturally occurring B-cell responses to breast cancer. Cancer Immunol Immunother 52(12):715–738

    Article  PubMed  Google Scholar 

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Correspondence to A. R. Green.

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Mahmoud, S.M.A., Lee, A.H.S., Paish, E.C. et al. The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat 132, 545–553 (2012). https://doi.org/10.1007/s10549-011-1620-1

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