A retrospective study of breast cancer subtypes: the risk of relapse and the relations with treatments

  • Yahong Wang
  • Quangui Yin
  • Qi Yu
  • Jing Zhang
  • Ziyu Liu
  • Shuling Wang
  • Shuhua Lv
  • Yun Niu
Clinical trial

Abstract

Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate relapse for patients with the major subtypes of breast cancer as classified using immunohistochemical assay and to investigate the patterns of benefit from the therapies over the past years. The study population included primary, operable 2,118 breast cancer patients, all non-specific infiltrative ductal carcinoma, with the median age of 53.2 years. All patients underwent local and/or systemic treatments. The clinicopathological characteristics and clinical outcomes were retrospectively reviewed. The expression of estrogen receptor (ER), progesterone receptor, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin 5/6 were analyzed by immunohistochemistry. All patients were classified into the following categories: luminal A, luminal B, HER2 overexpressing, basal-like, and unclassified subtypes. Ki-67 was detected in luminal A subtype. The median follow-up time was 67.9 months. Luminal A tumors had the lowest rate of relapse (12.7%, P < 0.001), while luminal B, HER2 overexpression, and basal-like subtypes were associated with an increased risk of relapse (15.7, 19.1, 20.9%). Molecular subtypes retained independent prognostic significance (P < 0.001). In luminal A subtype, adjunctive radiotherapy could decrease the risk of relapse (P = 0.005), Ki67 positive was a high-risk factor for relapse (P < 0.001), and adjuvant chemotherapies could reduce the relapse for the patients with risk factors (P < 0.001). Adjuvant hormone therapy was an effective treatment for ER-positive tumors (P < 0.001). Molecular subtypes of breast cancer could robustly identify the risk of recurrence and were significant in therapeutic decision making. The model combined subtype and clinical pathology was a significant improvement. Luminal A tumors might represent two distinct subsets which demonstrated distinct prognosis and therapy response.

Keywords

Breast cancer subtypes Risk factor Relapse Adjutant therapy 

Abbreviations

NCCN

National comprehensive cancer network

ER

Estrogen receptor

PR

Progesterone receptor

HER2

Human epidermal growth factor receptor 2

EGFR

Epidermal growth factor receptor

CI

Confidence interval HR Hazard ratio

IHC

Immunohistochemical

OS

Overall survival

RFS

Relapse-free survival

TNP

Triple negative phenotype

BCS

Breast-conserving surgery

References

  1. 1.
    Rakha EA, El-Sayed ME, Lee AH, Elston CW, Grainge MJ, Hodi Z, Blamey RW, Ellis IO (2008) Prognostic significance of Nottingham histologic grade in invasive breast carcinoma. J Clin Oncol 26:3153–3158PubMedCrossRefGoogle Scholar
  2. 2.
    Fitzgibbons PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, Ruby SG, O’Malley F, Simpson JF, Connolly JL, Hayes DF, Edge SB, Lichter A, Schnitt SJ (2000) Prognostic factors in breast cancer: college of American pathologists consensus statement 1999. Arch Pathol Lab Med 124:966–978PubMedGoogle Scholar
  3. 3.
    Anderson TJ, Alexander FE, Lamb J, Smith A, Forrest AP (2000) Pathology characteristics that optimize outcome prediction of a breast screening trial. Br J Cancer 83:487–492PubMedCrossRefGoogle Scholar
  4. 4.
    Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, Cronin M, Baehner FL, Watson D, Bryant J, Costantino JP, Geyer CE Jr, Wickerham DL, Wolmark N (2006) Gene expression and benefit of chemotherapy in women with node negative, estrogen receptor-positive breast cancer. J Clin Oncol 24:3726–3734PubMedCrossRefGoogle Scholar
  5. 5.
    Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, Livasy C, Carey LA, Reynolds E, Dressler L, Nobel A, Parker J, Ewend MG, Sawyer LR, Wu J, Liu Y, Nanda R, Tretiakova M, Ruiz Orrico A, Dreher D, Palazzo JP, Perreard L, Nelson E, Mone M, Hansen H, Mullins M, Quackenbush JF, Ellis MJ, Olopade OI, Bernard PS, Perou CM (2006) The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 7:96PubMedCrossRefGoogle Scholar
  6. 6.
    Loi S, Haibe-Kains B, Desmedt C, Lallemand F, Tutt AM, Gillet C, Ellis P, Harris A, Bergh J, Foekens JA, Klijn JG, Larsimont D, Buyse M, Bontempi G, Delorenzi M, Piccart MJ, Sotiriou C (2007) Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol 25:1239–1246PubMedCrossRefGoogle Scholar
  7. 7.
    Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lønning PE, Brown PO, Børresen-Dale AL, Botstein D (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423PubMedCrossRefGoogle Scholar
  8. 8.
    Rakha EA, El-Rehim DA, Paish C, Green AR, Lee AH, Robertson JF, Blamey RW, Macmillan D, Ellis IO (2006) Basal phenotype identifies a poor prognostic subgroup of breast cancer of clinical importance. Eur J Cancer 42:3149–3156PubMedCrossRefGoogle Scholar
  9. 9.
    Calza S, Hall P, Auer G, Bjöhle J, Klaar S, Kronenwett U, Liu ET, Miller L, Ploner A, Smeds J, Bergh J, Pawitan Y (2006) Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients. Breast Cancer Res 8:R34PubMedCrossRefGoogle Scholar
  10. 10.
    Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast cancer. Clin Cancer Res 10:5367–5374PubMedCrossRefGoogle Scholar
  11. 11.
    Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina breast cancer study. J Am Med Assoc 295:2492–2502CrossRefGoogle Scholar
  12. 12.
    Yu K, Lee CH, Tan PH, Tan P (2004) Conservation of breast cancer molecular subtypes and transcriptional patterns of tumor progression across distinct ethnic population. Clin Cancer Res 10:5508–5517PubMedCrossRefGoogle Scholar
  13. 13.
    Tang P, Skinner KA, Hicks DG (2009) Molecular classification of breast carcinomas by immunohistochemical analysis: are we ready? Diagn Mol Pathol 18:125–132PubMedCrossRefGoogle Scholar
  14. 14.
    Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474–1481PubMedGoogle Scholar
  15. 15.
    Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101:736–750PubMedCrossRefGoogle Scholar
  16. 16.
    Kurebayashi J, Moriya T, Ishida T, Hirakawa H, Kurosumi M, Akiyama F, Kinoshita T, Takei H, Takahashi K, Ikeda M, Nakashima K (2007) The prevalence of intrinsic subtypes and prognosis in breast cancer patients of different races. Breast 16:S72–S77PubMedCrossRefGoogle Scholar
  17. 17.
    Chlebowski RT, Chen Z, Anderson GL, Rohan T, Aragaki A, Lane D, Dolan NC, Paskett ED, McTiernan A, Hubbell FA, Adams-Campbell LL, Prentice R (2005) Ethnicity and breast cancer: factors influencing differences in incidence and outcome. J Natl Cancer Inst 97:439–448PubMedCrossRefGoogle Scholar
  18. 18.
    Nofech-Mozes S, Trudeau M, Kahn HK, Dent R, Rawlinson E, Sun P, Narod SA, Hanna WM (2009) Patterns of recurrence in the basal and non-basal subtypes of triple-negative breast cancers. Breast Cancer Res Treat 118:131–137PubMedCrossRefGoogle Scholar
  19. 19.
    Millar EK, Graham PH, O’Toole SA, McNeil CM, Browne L, Morey AL, Eggleton S, Beretov J, Theocharous C, Capp A, Nasser E, Kearsley JH, Delaney G, Papadatos G, Fox C, Sutherland RL (2009) Prediction of local recurrence, distant metastases, and death after breast-conserving therapy in earlystage invasive breast cancer using a five-biomarker panel. J Clin Oncol 27:4701–4708PubMedCrossRefGoogle Scholar
  20. 20.
    Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, Bellon JR, Wong JS, Smith BL, Harris JR (2008) Breast cancer subtype approximated by estrogen receptor, progesterone and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 26:2373–2379PubMedCrossRefGoogle Scholar
  21. 21.
    Voduc KD, Cheang MC, Tyldesley S, Gelmon K, Nielsen TO, Kennecke H (2010) Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol 28:1684–1691PubMedCrossRefGoogle Scholar
  22. 22.
    Crabb SJ, Cheang MC, Leung S, Immonen T, Nielsen TO, Huntsman DD, Bajdik CD, Chia SK (2008) Basal breast cancer molecular subtype predicts for lower incidence of axillary lymph node metastases in primary breast cancer. Clin Breast Cancer 8:249–256PubMedCrossRefGoogle Scholar
  23. 23.
    Urruticoechea A, Smith IE, Dowsett M (2005) Proliferation marker Ki-67 in early breast cancer. J Clin Oncol 23:7212–7220PubMedCrossRefGoogle Scholar
  24. 24.
    Colleoni M, Rotmensz N, Peruzzotti G, Maisonneuve P, Viale G, Renne G, Casadio C, Veronesi P, Intra M, Torrisi R, Goldhirsch A (2004) Minimal and small size invasive breast cancer with no axillary lymph node involvement: the need for tailored adjuvant therapies. Ann Oncol 15:1633–1639PubMedCrossRefGoogle Scholar
  25. 25.
    Mamounas EP, Tang G, Fisher B, Paik S, Shak S, Costantino JP, Watson D, Geyer CE Jr, Wickerham DL, Wolmark N (2010) Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20. J Clin Oncol 28(10):1677–1683PubMedCrossRefGoogle Scholar
  26. 26.
    Jager JJ, Jansen RL, Arends JW, Joosten-Achjanie S, Volovics L, Schouten LJ, De Jong JM, Meyenfeldt MF, Blijham GH (2000) Anti-apoptotic phenotype is associated with decreased locoregional recurrence rate in breast cancer. Anticancer Res 20:1269–1275PubMedGoogle Scholar
  27. 27.
    Truong PT, Lesperance M, Culhaci A, Kader HA, Speers CH, Olivotto IA (2005) Patient subsets with T1–T2, node-negative breast cancer at high locoregional recurrence risk after mastectomy. Int J Radiat Oncol Biol Phys 62:175–182PubMedCrossRefGoogle Scholar
  28. 28.
    Conforti R, Boulet T, Tomasic G, Taranchon E, Arriagada R, Spielmann M, Ducourtieux M, Soria JC, Tursz T, Delaloge S, Michiels S, Andre F (2007) Breast cancer molecular subclassification and estrogen receptor expression to predict efficacy of adjuvant anthracyclines-based chemotherapy: a biomarker study from two randomized trials. Ann Oncol 18:1477–1483PubMedCrossRefGoogle Scholar
  29. 29.
    Razzak AR, Lin NU, Winer EP (2008) Heterogeneity of breast cancer and implications of adjuvant chemotherapy. Breast Cancer 15:31–34PubMedCrossRefGoogle Scholar
  30. 30.
    Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, Quackenbush JF, Stijleman IJ, Palazzo J, Marron JS, Nobel AB, Mardis E, Nielsen TO, Ellis MJ, Perou CM, Bernard PS (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27:1160–1167PubMedCrossRefGoogle Scholar
  31. 31.
    Finetti P, Cervera N, Charafe-Jauffret E, Chabannon C, Charpin C, Chaffanet M, Jacquemier J, Viens P, Birnbaum D, Bertucci F (2008) Sixteen-kinase gene expression identifies luminal breast cancers with poor prognosis. Cancer Res 68:767–776PubMedCrossRefGoogle Scholar
  32. 32.
    Viale G, Regan MM, Mastropasqua MG, Maffini F, Maiorano E, Colleoni M, Price KN, Golouh R, Perin T, Brown RW, Kovács A, Pillay K, Ohlschlegel C, Gusterson BA, Castiglione-Gertsch M, Gelber RD, Goldhirsch A, Coates AS, International Breast Cancer Study Group (2008) Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J Natl Cancer Inst 100(3):207–212PubMedCrossRefGoogle Scholar
  33. 33.
    Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13:2329–2334PubMedCrossRefGoogle Scholar
  34. 34.
    Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, Morandi P, Fan C, Rabiul I, Ross JS, Hortobagyi GN, Pusztai L (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678–5685PubMedCrossRefGoogle Scholar
  35. 35.
    Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, Pusztai L (2008) Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26:1275–1281PubMedCrossRefGoogle Scholar
  36. 36.
    Berry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, Goldstein LJ, Martino S, Perez EA, Muss HB, Norton L, Hudis C, Winer EP (2006) Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658–1667PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Yahong Wang
    • 1
  • Quangui Yin
    • 2
  • Qi Yu
    • 1
    • 3
  • Jing Zhang
    • 1
  • Ziyu Liu
    • 1
  • Shuling Wang
    • 1
  • Shuhua Lv
    • 1
  • Yun Niu
    • 1
  1. 1.Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education and Key Laboratory of Cancer Prevention and Therapy of TianjinTianjin Medical University Cancer Institute and HospitalHexi District, TianjinChina
  2. 2.Department of EmergencyTai Ji Sun International Health Management CenterTianjinChina
  3. 3.Department of OncologyJinghai HospitalTianjinChina

Personalised recommendations