Breast Cancer Research and Treatment

, Volume 113, Issue 2, pp 357–370 | Cite as

Race and triple negative threats to breast cancer survival: a population-based study in Atlanta, GA

  • Mary Jo Lund
  • Katrina F. Trivers
  • Peggy L. Porter
  • Ralph J. Coates
  • Brian Leyland-Jones
  • Otis W. Brawley
  • Elaine W. Flagg
  • Ruth M. O’Regan
  • Sheryl G. A. Gabram
  • J. William Eley


Background Breast cancers with a triple negative tumor (TNT) subtype (as defined by lacking protein expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)) preclude the use of available targeted therapies and may contribute to poor outcome and to the historically poorest survival observed among African–American (AA) women. This study examines association of the ER/PR/HER2 subtypes with race and breast cancer survival. Methods Breast tumors from a population-based cohort of 116 AA and 360 white Atlanta women aged 20–54, diagnosed from 1990 to 1992 were centrally reviewed and tested by immunohistochemistry. Multivariate survival analyses within subtypes (TNT, ER−PR−HER2+, ER+/PR+HER2+, ER+/PR+HER2−) were conducted using weighted Cox regression and included socio-demographic, prognostic, and treatment factors. Results TNTs were more prevalent among young women and particularly among AA women (Odds Ratio [OR] = 1.9, 95% Confidence Interval [CI] 1.2–2.9), adjusting for age, stage, grade, and poverty index. Overall mortality was higher for AA women (Hazard Ratio [HR] = 1.9, 95% CI, 1.5–2.5) and differed by subtypes (P < 0.001). Within the TNT subtype, racial differences in survival persisted, after additional adjustment for treatment and comorbidities (HR = 2.0, 95% CI 1.0–3.7). TNTs were uniquely associated with high expression of p16, p53, and Cyclin E; and low Bcl-2 and Cyclin D1 expression. Conclusions The high prevalence of TNTs among younger women and particularly younger AA women, along with unique protein expression patterns and poorer survival, suggests varying gene–environment etiologies with respect to age and race/ethnicity and a need for effective therapies.


African–American Breast cancer Race Survival Triple negative Tumor subtypes 



Supported in part by awards RO1CA64292 (R.J.C., E.W.F., J.W.E., M.J.L.), RO1CA71735 (P.L.P.), the Avon Foundation (M.J.L., P.L.P.), the Glenn Foundation (M.J.L.), the Sindab Endowment (M.J.L., R.M.O.) and the Oak Ridge Institute for Science & Education Research Participation Program/CDC (M.J.L., K.F.T). The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.


  1. 1.
    Ries LAG, Melbert D, Krapcho M et al (2006) SEER cancer statistics review, 1975–2004. National Cancer Institute, Bethesda, MDGoogle Scholar
  2. 2.
    Amend K, Hicks D, Ambrosone C (2006) Breast cancer in African–American women: differences in tumor biology from European–American women. Cancer Res 66(17):8327–8330PubMedCrossRefGoogle Scholar
  3. 3.
    Chlebowski RT, Chen Z, Anderson GL et al (2006) Ethnicity and breast cancer: factors influencing differences in incidence and outcome. J Natl Cancer Inst 97(6):439–448Google Scholar
  4. 4.
    Eley JW, Hill HA, Chen VW et al (1994) Racial differences in survival from breast cancer. Results of the National Cancer Institute Black/White Cancer Survival Study. JAMA 272(12):947–954PubMedCrossRefGoogle Scholar
  5. 5.
    Jatoi I, Chen BE, Anderson WF, Rosenberg PS (2007) Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis. J Clin Oncol 25(13):1683–1690PubMedCrossRefGoogle Scholar
  6. 6.
    Newman LA, Griffith KA, Jatoi I et al (2006) Meta-analysis of survival in African American and white American patients with breast cancer: ethnicity compared with socioeconomic status. J Clin Oncol 24(9):1342–1349PubMedCrossRefGoogle Scholar
  7. 7.
    Shavers VL, Harlan LC, Stevens JL (2003) Racial/ethnic variation in clinical presentation, treatment, and survival among breast cancer patients under age 35. Cancer 97(1):134–147PubMedCrossRefGoogle Scholar
  8. 8.
    Wojcik BE, Spinks MK, Optenberg SA (1998) Breast carcinoma survival analysis for African American and white women in an equal-access health care system. Cancer 82(7):1310–1318PubMedCrossRefGoogle Scholar
  9. 9.
    Dayal HH, Power RN, Chiu C (1982) Race and socio-economic status in survival from Breast cancer. J Chronic Dis 35(8):675–683PubMedCrossRefGoogle Scholar
  10. 10.
    Abd El-Rehim DM, Ball G, Pinder SE 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):340–350PubMedCrossRefGoogle Scholar
  11. 11.
    Abd El-Rehim DM, Pinder SE, Paish CE et al (2004) Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol 203(2):661–671PubMedCrossRefGoogle Scholar
  12. 12.
    Sorlie T, Perou CM, Tibshirani R et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874PubMedCrossRefGoogle Scholar
  13. 13.
    Sorlie T, Tibshirani R, Parker J et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100(14):8418–8423PubMedCrossRefGoogle Scholar
  14. 14.
    Sorlie T, Wang Y, Xiao C et al (2006) Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analyses across three different platforms. BMC Genomics 7:127PubMedCrossRefGoogle Scholar
  15. 15.
    van‘t Veer LJ, Dai H, van de Vijver MJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer[comment]. Nature 415(6871):530–536CrossRefGoogle Scholar
  16. 16.
    Sotiriou C, Neo SY, McShane LM et al (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 100(18):10393–10398PubMedCrossRefGoogle Scholar
  17. 17.
    Birnbaum D, Bertucci F, Ginestier C et al (2004) Basal and luminal breast cancers: basic or luminous? (review). Int J Oncol 25(2):249–258PubMedGoogle Scholar
  18. 18.
    Carey LA, Perou CM, Livasy CA et al (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502PubMedCrossRefGoogle Scholar
  19. 19.
    Haffty BG, Yang Q, Reiss M et al (2006) Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 24(36):5652–5657PubMedCrossRefGoogle Scholar
  20. 20.
    Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752PubMedCrossRefGoogle Scholar
  21. 21.
    Sotiriou C, Wirapati P, Loi S et al (2006) Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst 98(4):262–272PubMedCrossRefGoogle Scholar
  22. 22.
    Yang XR, Sherman ME, Rimm DL et al (2007) Differences in risk factors for breast cancer molecular subtypes in a population-based study. CEBP 16(3):439–443Google Scholar
  23. 23.
    Cleator S, Heller W, Coombes RC (2007) Triple-negative breast cancer: therapeutic options. Lancet Oncol 8(3):235–244PubMedCrossRefGoogle Scholar
  24. 24.
    Rakha EA, El-Rehim DA, Paish C et al (2006) Basal phenotype identifies a poor prognostic subgroup of breast cancer of clinical importance. Eur J Cancer 42(18):3149–3156PubMedCrossRefGoogle Scholar
  25. 25.
    Nielsen TO, Hsu FD, Jensen K et al (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374PubMedCrossRefGoogle Scholar
  26. 26.
    Anderson WF, Matsuno R (2006) Breast cancer heterogeneity: a mixture of at least two main types?[comment]. J Natl Cancer Inst 98(14):948–951PubMedCrossRefGoogle Scholar
  27. 27.
    Rakha EA, El-Sayed ME, Green AR et al (2007) Prognostic markers in triple-negative breast cancer. Cancer 109(1):25–32PubMedCrossRefGoogle Scholar
  28. 28.
    Bauer KR, Brown M, Cress RD et al (2007) Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2–negative invasive breast cancer, the so-called triple-negative phenotype: A population-based study from the California cancer Registry. Cancer 109(9):1721–1728PubMedCrossRefGoogle Scholar
  29. 29.
    Morris GJ, Naidu S, Topham AK et al (2007) Differences in breast carcinoma characteristics in newly diagnosed African–American and Caucasian patients: a single-institution compilation compared with the National Cancer Institute’s Surveillance, Epidemiology, and End Results database. Cancer 110(4):876–884PubMedCrossRefGoogle Scholar
  30. 30.
    Stark A, Kapke A, Schultz D (2007) Advanced stages and poorly differentiated grade are associated with an increased risk of HER2/neu positive breast carcinoma only in White women: findings from a prospective cohort study of African–American and White-American women. Breast Cancer Res Treat [epub ahead of print]Google Scholar
  31. 31.
    Porter PL, Lund MJ, Lin MG et al (2004) Racial differences in expression of cell cycle regulatory proteins in breast cancer: Study of young African American and white women in Atlanta. Cancer 100(12):2533–2542PubMedCrossRefGoogle Scholar
  32. 32.
    Brinton LA, Daling JR, Liff JM et al (1995) Oral contraceptives and breast cancer risk among younger women. J Natl Cancer Inst 87(11):827–835PubMedCrossRefGoogle Scholar
  33. 33.
    Gwyn K, Bondy ML, Cohen DS et al (2004) Racial differences in diagnosis, treatment, and clinical delays in a population-based study of patients with newly diagnosed breast carcinoma. Cancer 100(8):1595–1604PubMedCrossRefGoogle Scholar
  34. 34.
    Department of Health, Human Services. (1991) HHS poverty guidelines. Fed Regist 47:15417–15418Google Scholar
  35. 35.
    SEER Summary Staging Manual (2000) Codes and coding instructions. National Cancer Institute, Bethesda, MDGoogle Scholar
  36. 36.
    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):403–410PubMedCrossRefGoogle Scholar
  37. 37.
    Tavassoli FA, Deville P, Aas T (2003) Pathology and genetics of tumours of the breast and female genital organs. Oxford University Press, OxfordGoogle Scholar
  38. 38.
    Cattoretti G, Becker M, Key G et al (1992) Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol 168(4):357–363PubMedCrossRefGoogle Scholar
  39. 39.
    Gerdes J, Becker MH, Key G et al (1992) Immunohistological detection of tumour growth fraction (Ki-67 antigen) in formalin-fixed and routinely processed tissues.[see comment]. J Pathol 168(1):85–86PubMedCrossRefGoogle Scholar
  40. 40.
    Hsu SM, Raine L, Fanger H (1981) Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures[see comment]. J Histochem Cytochem 29(4):577–580PubMedGoogle Scholar
  41. 41.
    Hsu SM, Soban E (1982) Color modification of diaminobenzidine (DAB) precipitation by metallic ions and its application for double immunohistochemistry. J Histochem Cytochem 30(10):1079–1082PubMedGoogle Scholar
  42. 42.
    Taylor CR, Shi SR, Chaiwun B et al (1994) Strategies for improving the immunohistochemical staining of various intranuclear prognostic markers in formalin- paraffin sections: androgen receptor, estrogen receptor, progesterone receptor, p53 protein, proliferating cell nuclear antigen, and Ki-67 antigen revealed by antigen retrieval techniques[see comment]. Human Pathol 25(3):263–270CrossRefGoogle Scholar
  43. 43.
    Andersen J, Poulsen HS (1989) Immunohistochemical estrogen receptor determination in paraffin-embedded tissue. Prediction of response to hormonal treatment in advanced breast cancer. Cancer 64(9):1901–1908PubMedCrossRefGoogle Scholar
  44. 44.
    Parl FF, Posey YF (1988) Discrepancies of the biochemical and immunohistochemical estrogen receptor assays in breast cancer. Human Pathol 19(8):960–966CrossRefGoogle Scholar
  45. 45.
    Shousha S, Stamp T, James K et al (1989) Immunohistochemical study of oestrogen receptors in breast carcinomas that are biochemically receptor negative. J Clin Pathol 43:239–242Google Scholar
  46. 46.
    Giri D, Goepel J, Rogers K (1988) Immunohistological demonstration of progesterone receptor in breast carninomas: correlation with radioligand binding assays and oestrogen receptor negative. J Clin Pathol 41:444–447Google Scholar
  47. 47.
    Press MF, Hung G, Godolphin W et al (1994) Sensitivity of HER-2/neu antibodies in archival tissue samples: potential source of error in immunohistochemical studies of oncogene expression. Cancer Res 54(10):2771–2777PubMedGoogle Scholar
  48. 48.
    Bartek J, Bartkova J, Vojtesek B et al (1990) Patterns of expression of the p53 tumour suppressor in human breast tissues and tumours in situ and in vitro. Int J Cancer 46(5):839–844PubMedCrossRefGoogle Scholar
  49. 49.
    Davidoff AM, Herndon JE 2nd, Glover NS et al (1991) Relation between p53 overexpression and established prognostic factors in breast cancer. Surgery 110(2):259–264PubMedGoogle Scholar
  50. 50.
    Purdie CA, O’Grady J, Piris J et al (1991) p53 expression in colorectal tumors. Am J Pathol 138(4):807–813PubMedGoogle Scholar
  51. 51.
    Ohtsubo M, Theodoras AM, Schumacher J et al (1995) Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol 15(5):2612–2624PubMedGoogle Scholar
  52. 52.
    Porter PL, Malone KE, Heagerty PJ et al (1997) Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med 3(2):222–225PubMedCrossRefGoogle Scholar
  53. 53.
    Motokura T, Bloom T, Kim HG et al (1991) A novel cyclin encoded by a bcl1-linked candidate oncogene [see comment]. Nature 350(6318):512–515PubMedCrossRefGoogle Scholar
  54. 54.
    Simpson JF, Quan DE, O’Malley F et al (1997) Amplification of CCND1 and expression of its protein product, cyclin D1, in ductal carcinoma in situ of the breast. Am J Pathol 151(1):161–168PubMedGoogle Scholar
  55. 55.
    Geradts J, Hruban RH, Schutte M et al (2000) Immunohistochemical p16INK4a analysis of archival tumors with deletion, hypermethylation, or mutation of the CDKN2/MTS1 gene. A comparison of four commercial antibodies. Appl Immunohistochem Mol Morphol 8(1):71–79PubMedCrossRefGoogle Scholar
  56. 56.
    Barbareschi M, Caffo O, Doglioni C et al (1996) p21WAF1 immunohistochemical expression in breast carcinoma: correlations with clinicopathological data, oestrogen receptor status, MIB1 expression, p53 gene and protein alterations and relapse-free survival. Br J Cancer 74(2):208–215Google Scholar
  57. 57.
    Cote RJ, Shi Y, Groshen S et al (1998) Association of p27Kip1 levels with recurrence and survival in patients with stage C prostate carcinoma. J Natl Cancer Inst 90(12):916–920PubMedCrossRefGoogle Scholar
  58. 58.
    Fusaro G, Wang S, Chellappan S (2002) Differential regulation of Rb family proteins and prohibitin during camptothecin-induced apoptosis. Oncogene 21(29):4539–4548PubMedCrossRefGoogle Scholar
  59. 59.
    Saegusa M, Hashimura M, Kuwata T et al (2006) Induction of p16INK4A mediated by beta-catenin in a TCF4-independent manner: implications for alterations in p16INK4A and pRb expression during trans-differentiation of endometrial carcinoma cells. Int J Cancer 119(10):2294–2303PubMedCrossRefGoogle Scholar
  60. 60.
    Zutter M, Hockenbery D, Silverman GA et al (1991) Immunolocalization of the Bcl-2 protein within hematopoietic neoplasms. Blood 78(4):1062–1068PubMedGoogle Scholar
  61. 61.
    Negoescu A, Lorimier P, Labat-Moleur F et al (1996) In situ apoptotic cell labeling by the TUNEL method: improvement and evaluation on cell preparations. J Histochem Cytochem 44(9):959–968PubMedGoogle Scholar
  62. 62.
    Birner P, Oberhuber G, Stani J et al (2001) Evaluation of the United States Food and Drug Administration-approved scoring and test system of HER-2 protein expression in breast cancer. Clin Cancer Res 7(6):1669–1975PubMedGoogle Scholar
  63. 63.
    Sorlie T. (2004) Molecular portraits of breast cancer: tumour subtypes as distinct disease entities. Euro J Cancer 40(18):2667–2675CrossRefGoogle Scholar
  64. 64.
    Kleinbaum DG (1996) Survival analysis – a self-learning text. Springer-Verlag, New YorkGoogle Scholar
  65. 65.
    Fregene A, Newman LA (2005) Breast cancer in sub-Saharan Africa: how does it relate to breast cancer in African–American women? Cancer 103(8):1540–1550PubMedCrossRefGoogle Scholar
  66. 66.
    Olopade OI, Ikpatt FO, Dignam JJ et al (2004) “Intrinsic Gene Expression” subtypes correlated with grade and morphometric parameters reveal a high proportion of aggressive basal-like tumors among black women of African ancestry. J Clin Oncol (Meeting Abstracts) 22(14 suppl):9509Google Scholar
  67. 67.
    Millikan RC, Newman B, Tse CK et al (2007) Epidemiology of basal-like breast cancer. Breast Cancer Res Treat [epub ahead of print]Google Scholar
  68. 68.
    Yehiely F, Moyano JV, Evans JR et al (2006) Deconstructing the molecular portrait of basal-like breast cancer. Trend Mol Med 12(11):537–5544CrossRefGoogle Scholar
  69. 69.
    Foulkes WD, Brunet JS, Stefansson IM et al (2004) The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res 64(3):830–835PubMedCrossRefGoogle Scholar
  70. 70.
    Tan DS, Marchio C, Jones RL et al (2006) Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast Cancer Res Treat [epub ahead of print]Google Scholar
  71. 71.
    Romond EH, Perez EA, Bryant J et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.[see comment]. N Engl J Med 353(16):1673–1684PubMedCrossRefGoogle Scholar
  72. 72.
    Slamon DJ, Romond EH, Perez EA et al (2006) Advances in adjuvant therapy for breast cancer. Clin Adv Hematol Oncol 4(suppl 1):4–9 [discussion suppl 10]Google Scholar
  73. 73.
    Spitz MR, Wu X, Mills G (2005) Integrative epidemiology: from risk assessment to outcome prediction. J Clin Oncol 23(2):267–275PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Mary Jo Lund
    • 1
    • 2
    • 3
    • 4
  • Katrina F. Trivers
    • 5
  • Peggy L. Porter
    • 6
  • Ralph J. Coates
    • 5
  • Brian Leyland-Jones
    • 2
    • 3
  • Otis W. Brawley
    • 1
    • 2
    • 3
    • 4
  • Elaine W. Flagg
    • 7
  • Ruth M. O’Regan
    • 2
    • 3
  • Sheryl G. A. Gabram
    • 3
    • 4
  • J. William Eley
    • 2
    • 3
  1. 1.Department of Epidemiology, Rollins School of Public HealthEmory UniversityAtlantaUSA
  2. 2.Hematology and OncologyEmory University School of MedicineAtlantaUSA
  3. 3.Winship Cancer InstituteEmory University School of MedicineAtlantaUSA
  4. 4.Georgia Cancer Center for Excellence at GradyEmory UniversityAtlantaUSA
  5. 5.Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health PromotionCenters for Disease Control and PreventionAtlantaUSA
  6. 6.Division of Human BiologyFred Hutchinson Cancer Research CenterSeattleUSA
  7. 7.Division of HIV/AIDS PreventionCenters for Disease Control and PreventionAtlantaUSA

Personalised recommendations