Medical Oncology

, Volume 29, Issue 3, pp 1536–1542

Coexisting ductal carcinoma in situ independently predicts lower tumor aggressiveness in node-positive luminal breast cancer

  • H. Wong
  • S. Lau
  • R. Leung
  • J. Chiu
  • P. Cheung
  • T. T. Wong
  • R. Liang
  • R. J. Epstein
  • T. Yau
Original Paper

Abstract

Primary breast invasive ductal carcinoma coexisting with ductal carcinoma in situ (IDC-DCIS) is characterized by lower proliferation rate and metastatic propensity than size-matched pure IDC. IDC-DCIS is also more often ER-positive, PR-positive and/or HER2-positive. This analysis aims to clarify whether the presence of coexisting DCIS in IDC affects tumor aggressiveness in various biological subtypes of breast cancer, respectively. Tumor data obtained from 1,355 consecutive female patients undergoing upfront surgery for primary breast cancer were analyzed retrospectively; 196 patients with pure DCIS were excluded. Based on evidence that immunohistochemistry (IHC) provides a reasonable approximation of molecular phenotypes, the tumor samples were divided into 4 groups: (1) luminal A (ER and/or PR-positive, HER2-negative, Ki67 ≤ 12), (2) luminal B (ER and/or PR-positive, HER2-negative, Ki67 > 12), (3) HER2 (HER2-positive) and (4) basal-like (triple-negative) disease. Ki67 expression and nodal involvement of IDC with or without DCIS in these groups were compared. The number of patients with luminal A, luminal B, HER2 and basal-like breast cancer were 396, 265, 258 and 117, respectively. Ki-67 was lower in IDC-DCIS than in size-adjusted pure IDC of both luminal A and luminal B subtypes (P = 0.15 and <0.005, respectively). In HER2 or basal-like tumors, there were no significant difference between pure IDC and IDC-DCIS. The presence of coexisting DCIS in IDC predicts lower biological aggressiveness in luminal cancers but not in the conventionally more aggressive HER2-positive and triple-negative subtypes.

Keywords

Ductal carcinoma in situ (DCIS) Invasive ductal carcinoma (IDC) Ki67 Luminal breast cancer 

References

  1. 1.
    Jo BH, Chun YK. Heterogeneity of invasive ductal carcinoma: proposal for a hypothetical classification. J Korean Med Sci. 2006;21:460–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Leong AS, Sormunen RT, Vinyuvat S, et al. Biologic markers in ductal carcinoma in situ and concurrent infiltrating carcinoma. A comparison of eight contemporary grading systems. Am J Clin Pathol. 2001;115:709–18.PubMedCrossRefGoogle Scholar
  3. 3.
    Warnberg F, Nordgren H, Bergkvist L, Holmberg L. Tumour markers in breast carcinoma correlate with grade rather than with invasiveness. Br J Cancer. 2001;85:869–74.PubMedCrossRefGoogle Scholar
  4. 4.
    Steinman S, Wang J, Bourne P, Yang Q, Tang P. Expression of cytokeratin markers, ER-alpha, PR, HER-2/neu, and EGFR in pure ductal carcinoma in situ (DCIS) and DCIS with co-existing invasive ductal carcinoma (IDC) of the breast. Ann Clin Lab Sci. 2007;37:127–34.PubMedGoogle Scholar
  5. 5.
    Schorr MC, Pedrini JL, Savaris RF, Zettler CG. Are the pure in situ breast ductal carcinomas and those associated with invasive carcinoma the same? Appl Immunohistochem Mol Morphol. 2010;18:51–4.PubMedCrossRefGoogle Scholar
  6. 6.
    Iakovlev V, Arneson N, Wong V, Wang C, Leung S, Iokovleva G, Warren K, Pintilie M, Done S. Genomic differences between pure ductal carcinoma in situ of the breast and that associated with invasive disease: a calibrated aCGH study. Clin Cancer Res. 2008;14:4446–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Aubele M, Mattis A, Zitzelsberger H, Walch A, Kremer M, Welzl G, Hofler H, Werner M. Extensive ductal carcinoma in situ with small foci of invasive ductal carcinoma: evidence of genetic resemblance by CGH. Int J Cancer. 2000;85:82–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Castro NP, Osorio C, Torres C, et al. Evidence that molecular changes in cells occur before morphological alterations during the progression of breast ductal carcinoma. Breast Cancer Res. 2008;10:R87. Epub.Google Scholar
  9. 9.
    Wong H, Lau S, Yau T, et al. Presence of an in situ component is associated with reduced biological aggressiveness of size-matched invasive breast cancer. Br J Cancer. 2010;102:1391–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Mylonas I, Makovitzky J, Jeschke U, Briese V, Friese K, Gerber B. Expression of Her2/neu, steroid receptors (ER and PR), Ki67 and p53 in invasive mammary ductal carcinoma associated with ductal carcinoma in situ (DCIS) versus invasive breast cancer alone. Anticancer Res. 2005;25:1719–23.PubMedGoogle Scholar
  11. 11.
    Papantoniou V, Sotiropoulou E, Valsamaki P, et al. Breast density, scintimammographic (99 m)Tc(V)DMSA uptake, and calcitonin gene related peptide (CGRP) expression in mixed invasive ductal associated with extensive in situ ductal carcinoma (IDC + DCIS) and pure invasive ductal carcinoma (IDC): correlation with estrogen receptor (ER) status, proliferation index Ki-67, and histological grade. Breast Cancer. 2010. [Epub ahead of print].Google Scholar
  12. 12.
    Chagpar AB, McMasters KM, Sahoo S, Edwards MJ. Does ductal carcinoma in situ accompanying invasive carcinoma affect prognosis? Surgery. 2009;146:561–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Onitilo AA, Engel JM, Greenlee RT, Mukesh BN. Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res. 2009;7:4–13.PubMedCrossRefGoogle Scholar
  15. 15.
    Cheang MC, Chia SK, Voduc D, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009;101:736–50.PubMedCrossRefGoogle Scholar
  16. 16.
    Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10:5367–74.PubMedCrossRefGoogle Scholar
  17. 17.
    Livasy CA, Karaca G, Nanda R, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol. 2006;19:264–71.PubMedCrossRefGoogle Scholar
  18. 18.
    Abd El-Rehim DM, Ball G, Pinder SE, et al. 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. 2005;116:340–50.PubMedCrossRefGoogle Scholar
  19. 19.
    Fitzgibbons PL, Page DL, Weaver D, et al. Prognostic factors in breast cancer. College of American pathologists consensus statement 1999. Arch Pathol Lab Med. 2000;124:966–78.PubMedGoogle Scholar
  20. 20.
    Jung SY, Han W, Lee JW, Ko E, Kim E, Yu JH, Moon HG, Park IA, Oh DY, Im SA, Kin TY, Hwang KT, Kin SW, Noh DY. Ki-67 expression gives additional prognostic information on St. Gallen 2007 and adjuvant! online risk categories in early breast cancer. Ann Surg Oncol. 2009;16:1112–21. 14 Feb 2009 Online.PubMedCrossRefGoogle Scholar
  21. 21.
    Penault-Llorca F, Andre F, Sagan C, et al. Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009;27:2809–15.PubMedCrossRefGoogle Scholar
  22. 22.
    Bouzubar N, Walker KJ, Griffiths K, Ellis IO, Elston CW, Robertson JF, Blamey RW, Nicholson RI. Ki67 immunostaining in primary breast cancer: pathological and clinical associations. Br J Cancer. 1989;59:943–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Barnard NJ, Hall PA, Lemoine NR, Kadar N. Proliferative index in breast carcinoma determined in situ by Ki67 immunostaining and its relationship to clinical and pathological variables. J Pathol. 1987;152:287–95.PubMedCrossRefGoogle Scholar
  24. 24.
    Locker AP, Birrell K, Bell JA, Nicholson RI, Elston CW, Blamey RW, Ellis IO. Ki67 immunoreactivity in breast carcinoma: relationships to prognostic variables and short term survival. Eur J Surg Oncol. 1992;18:224–9.PubMedGoogle Scholar
  25. 25.
    Yerushalmi R, Woods R, Ravdin PM, et al. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 2010;11:174–83.PubMedCrossRefGoogle Scholar
  26. 26.
    McClelland RA, Finlay P, Walker KJ, et al. Automated quantitation of immunocytochemically localized estrogen receptors in human breast cancer. Cancer Res. 1990;50:3545–50.PubMedGoogle Scholar
  27. 27.
    Sauter G, Lee J, Bartlett JM, et al. Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations. J Clin Oncol. 2009;27:1323–33.PubMedCrossRefGoogle Scholar
  28. 28.
    Breast cancer facts in Hong Kong report: report no. 2 (2010 issue). Hong Kong breast cancer registry. Available from: http://www.hkbcf.org/data.php?aid=113&did=126&lang=eng.
  29. 29.
    Montemurro F, Aglietta M. Hormone receptor-positive early breast cancer: controversies in the use of adjuvant chemotherapy. Endocr Relat Cancer. 2009;16:1091–102.PubMedCrossRefGoogle Scholar
  30. 30.
    Hassett MJ, Hughes ME, Niland JC, et al. Chemotherapy use for hormone receptor-positive, lymph node-negative breast cancer. J Clin Oncol. 2008;26:5553–60.PubMedCrossRefGoogle Scholar
  31. 31.
    Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352:930–42.Google Scholar
  32. 32.
    Albain KS, Barlow WE, Ravdin PM, et al. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009;374:2055–63.PubMedCrossRefGoogle Scholar
  33. 33.
    Albain KS. Adjuvant chemotherapy for lymph node-negative, estrogen receptor-negative breast cancer: a tale of three trials. J Natl Cancer Inst. 2004;96:1801–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Pagani O, Gelber S, Simoncini E, et al. Is adjuvant chemotherapy of benefit for postmenopausal women who receive endocrine treatment for highly endocrine-responsive, node-positive breast cancer? International breast cancer study group trials VII and 12–93. Breast Cancer Res Treat. 2009;116:491–500.PubMedCrossRefGoogle Scholar
  35. 35.
    Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726–34.PubMedCrossRefGoogle Scholar
  36. 36.
    van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009.PubMedCrossRefGoogle Scholar
  37. 37.
    Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11:55–65.PubMedCrossRefGoogle Scholar
  38. 38.
    Lo SS, Mumby PB, Norton J, et al. Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection. J Clin Oncol. 2010;28:1671–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Lacroix M, Toillon RA, Leclercq G. Stable ‘portrait’ of breast tumors during progression: data from biology, pathology and genetics. Endocr Relat Cancer. 2004;11:497–522.PubMedCrossRefGoogle Scholar
  40. 40.
    Glockner S, Lehmann U, Wilke N, et al. Amplification of growth regulatory genes in intraductal breast cancer is associated with higher nuclear grade but not with the progression to invasiveness. Lab Invest. 2001;81:565–71.PubMedCrossRefGoogle Scholar
  41. 41.
    Buerger H, Simon R, Schafer KL, et al. Genetic relation of lobular carcinoma in situ, ductal carcinoma in situ, and associated invasive carcinoma of the breast. Mol Pathol. 2000;53:118–21.PubMedCrossRefGoogle Scholar
  42. 42.
    Lehmann U, Langer F, Feist H, et al. Quantitative assessment of promoter hypermethylation during breast cancer development. Am J Pathol. 2002;160:605–12.PubMedCrossRefGoogle Scholar
  43. 43.
    Borresen-Dale AL. TP53 and breast cancer. Hum Mutat. 2003;21:292–300.PubMedCrossRefGoogle Scholar
  44. 44.
    Osborne C, Wilson P, Tripathy D. Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications. Oncologist. 2004;9:361–77.PubMedCrossRefGoogle Scholar
  45. 45.
    Hudziak RM, Schlessinger J, Ullrich A. Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc Natl Acad Sci USA. 1987;84:7159–63.PubMedCrossRefGoogle Scholar
  46. 46.
    Di Fiore PP, Pierce JH, Kraus MH, et al. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science. 1987;237:178–82.PubMedCrossRefGoogle Scholar
  47. 47.
    Chazin VR, Kaleko M, Miller AD, Slamon DJ. Transformation mediated by the human HER-2 gene independent of the epidermal growth factor receptor. Oncogene. 1992;7:1859–66.PubMedGoogle Scholar
  48. 48.
    Pietras RJ, Arboleda J, Reese DM, et al. HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene. 1995;10:2435–46.PubMedGoogle Scholar
  49. 49.
    Banerjee S, Reis-Filho JS, Ashley S, et al. Basal-like breast carcinomas: clinical outcome and response to chemotherapy. J Clin Pathol. 2006;59:729–35.PubMedCrossRefGoogle Scholar
  50. 50.
    Cheang MC, Voduc D, Bajdik C, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res. 2008;14:1368–76.PubMedCrossRefGoogle Scholar
  51. 51.
    Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.PubMedCrossRefGoogle Scholar
  52. 52.
    Bhargava R, Dabbs DJ. Luminal B breast tumors are not HER2 positive. Breast Cancer Res. 2008;10:404. author reply 405.PubMedCrossRefGoogle Scholar
  53. 53.
    Tang P, Skinner KA, Hicks DG. Molecular classification of breast carcinomas by immunohistochemical analysis: are we ready? Diagn Mol Pathol. 2009;18:125–32.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • H. Wong
    • 1
  • S. Lau
    • 2
  • R. Leung
    • 1
  • J. Chiu
    • 1
  • P. Cheung
    • 2
  • T. T. Wong
    • 2
  • R. Liang
    • 2
  • R. J. Epstein
    • 3
  • T. Yau
    • 1
    • 4
  1. 1.Division of Hematology and Oncology, Department of MedicineThe University of Hong KongPokfulam, Hong KongChina
  2. 2.Comprehensive Oncology CentreHong Kong Sanatorium HospitalHong KongChina
  3. 3.Department of OncologySt. Vincent’s HospitalSydneyAustralia
  4. 4.Department of SurgeryThe University of Hong KongHong KongChina

Personalised recommendations