Breast Cancer Research and Treatment

, Volume 124, Issue 1, pp 187–194 | Cite as

The association between biological subtype and locoregional recurrence in newly diagnosed breast cancer

  • Zsolt Gabos
  • John Thoms
  • Sunita Ghosh
  • John Hanson
  • Jean Deschênes
  • Siham Sabri
  • Bassam Abdulkarim
Clinical trial


We investigated the association between the risk of locoregional recurrence (LRR) and biological subtypes defined by hormonal receptors (HR) and HER-2 status in women with invasive breast cancer (BC). A total of 618 newly diagnosed BC patients were identified from a cancer registry within a single institution with standardized methods of tumor assessment for estrogen receptor (ER), progesterone receptor (PR), and HER-2. Patients were stratified based on surgical treatment, breast-conserving therapy (BCT) versus modified radical mastectomy (MRM), as well as biological subtypes: HR+/HER-2− (ER-positive or PR-positive, HER-2-negative), HR+/HER-2+ (ER-positive or PR-positive, HER-2-positive), HR−/HER-2+ (ER-negative and PR-negative, HER-2-positive) and TN (ER-negative, PR-negative and HER-2-negative). The association between clinicopathological factors, biological subtype and LRR was evaluated with univariate and multivariate Cox analysis. With a median follow-up of 4.8 years, the rate of LRR was 7.5%. On multivariate analysis, TN, tumor size ≥2 cm and lymph node (LN) positivity were associated with increased risk of LRR (P = 0.023, P = 0.048, and P = 0.0034, respectively). In BCT group, HR−/HER-2+ and LN positivity were associated with increased risk of LRR (HR 11.13; 95% CI 2.78–44.53; P = 0.0007 and HR 5.40; 95% CI 1.67–17.43; P = 0.0048, respectively). In MRM group, TN subtype and LN positivity were associated with increased risk of LRR (HR 4.72; 95% CI 1.53–14.52; P = 0.0069 and HR 3.23; 95% CI 1.44–7.29; P = 0.0047, respectively). Compared to HR+/HER-2−, HR−/HER-2+ treated by BCT and TN treated by MRM showed a significant decrease of 5-year LRR free survival (P = 0.0002 and P = 0.002, respectively). Tumor profiling using ER, PR, and HER-2 biomarkers is a promising tool to identify patients at high risk of LRR based on surgical treatment. Our findings suggest a different follow-up and locoregional treatment for patients with HR−/HER-2+ and TN subtypes.


Breast cancer HR−/HER-2+ and TN subtype Locoregional recurrence 



We thank the members of Alberta Cancer Registry for the identification of this population of breast cancer and the technicians from Department of Laboratory Medicine and Pathology for their support in immunohistochemistry.

Conflict of interest



  1. 1.
    Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752CrossRefPubMedGoogle Scholar
  2. 2.
    Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874CrossRefPubMedGoogle Scholar
  3. 3.
    van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ et al (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347(25):1999–2009CrossRefPubMedGoogle Scholar
  4. 4.
    Chang HY, Nuyten DS, Sneddon JB, Hastie T, Tibshirani R, Sorlie T, Dai H, He YD, van’t Veer LJ, Bartelink H et al (2005) Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc Natl Acad Sci USA 102(10):3738–3743CrossRefPubMedGoogle Scholar
  5. 5.
    Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, Talantov D, Timmermans M, Meijer-van Gelder ME, Yu J et al (2005) Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365(9460):671–679PubMedGoogle Scholar
  6. 6.
    Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351(27):2817–2826CrossRefPubMedGoogle Scholar
  7. 7.
    Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100(14):8418–8423CrossRefPubMedGoogle Scholar
  8. 8.
    Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, Martiat P, Fox SB, Harris AL, Liu ET (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 100(18):10393–10398CrossRefPubMedGoogle Scholar
  9. 9.
    Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H, van de Vijver MJ (2007) Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res 9(5):R65CrossRefPubMedGoogle Scholar
  10. 10.
    Bertucci F, Finetti P, Rougemont J, Charafe-Jauffret E, Cervera N, Tarpin C, Nguyen C, Xerri L, Houlgatte R, Jacquemier J et al (2005) Gene expression profiling identifies molecular subtypes of inflammatory breast cancer. Cancer Res 65(6):2170–2178CrossRefPubMedGoogle Scholar
  11. 11.
    Gabos Z, Sinha R, Hanson J, Chauhan N, Hugh J, Mackey JR, Abdulkarim B (2006) Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer. J Clin Oncol 24(36):5658–5663CrossRefPubMedGoogle Scholar
  12. 12.
    Levine M (2001) Clinical practice guidelines for the care and treatment of breast cancer: adjuvant systemic therapy for node-negative breast cancer (summary of the 2001 update). CMAJ 164(2):213PubMedGoogle Scholar
  13. 13.
    Truong PT, Olivotto IA, Whelan TJ, Levine M (2004) Clinical practice guidelines for the care and treatment of breast cancer: 16. Locoregional post-mastectomy radiotherapy. CMAJ 170(8):1263–1273PubMedGoogle Scholar
  14. 14.
    Whelan T, Olivotto I, Levine M (2003) Clinical practice guidelines for the care and treatment of breast cancer: breast radiotherapy after breast-conserving surgery (summary of the 2003 update). CMAJ 168(4):437–439PubMedGoogle Scholar
  15. 15.
    Shenkier T, Weir L, Levine M, Olivotto I, Whelan T, Reyno L (2004) Clinical practice guidelines for the care and treatment of breast cancer: 15. Treatment for women with stage III or locally advanced breast cancer. CMAJ 170(6):983–994PubMedGoogle Scholar
  16. 16.
    Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, Jeong JH, Wolmark N (2002) Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347(16):1233–1241CrossRefPubMedGoogle Scholar
  17. 17.
    Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, Aguilar M, Marubini E (2002) Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347(16):1227–1232CrossRefPubMedGoogle Scholar
  18. 18.
    Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P et al (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11(16):5678–5685CrossRefPubMedGoogle Scholar
  19. 19.
    Millar EK, Graham PH, O’Toole SA, McNeil CM, Browne L, Morey AL, Eggleton S, Beretov J, Theocharous C, Capp A et al (2009) Prediction of local recurrence, distant metastases, and death after breast-conserving therapy in early-stage invasive breast cancer using a five-biomarker panel. J Clin Oncol 27(28):4701–4708CrossRefPubMedGoogle Scholar
  20. 20.
    Gonzalez-Angulo AM, Litton JK, Broglio KR, Meric-Bernstam F, Rakkhit R, Cardoso F, Peintinger F, Hanrahan EO, Sahin A, Guray M et al (2009) High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol 27(34):5700–5706CrossRefPubMedGoogle Scholar
  21. 21.
    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 receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 26(14):2373–2378CrossRefPubMedGoogle Scholar
  22. 22.
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353(16):1673–1684CrossRefPubMedGoogle Scholar
  23. 23.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659–1672CrossRefPubMedGoogle Scholar
  24. 24.
    Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling J, Cheang MC, Gelmon K, Nielsen TO, Blomqvist C et al (2010) Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10, 159 cases from 12 studies. PLoS Med 7(5):e1000279CrossRefPubMedGoogle Scholar
  25. 25.
    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(10):1684–1691CrossRefPubMedGoogle Scholar
  26. 26.
    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(3):249–256CrossRefPubMedGoogle Scholar
  27. 27.
    Foulkes WD, Reis-Filho JS, Narod SA (2010) Tumor size and survival in breast cancer—a reappraisal. Nat Rev 7:348–353Google Scholar
  28. 28.
    Kyndi M, Sorensen FB, Knudsen H, Overgaard M, Nielsen HM, Overgaard J (2008) Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group. J Clin Oncol 26(9):1419–1426CrossRefPubMedGoogle Scholar
  29. 29.
    Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S et al (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502CrossRefPubMedGoogle Scholar
  30. 30.
    Albain KS, Barlow WE, Shak S, Hortobagyi GN, Livingston RB, Yeh IT, Ravdin P, Bugarini R, Baehner FL, Davidson NE et al (2010) 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 11(1):55–65CrossRefPubMedGoogle Scholar
  31. 31.
    Mamounas EP (2005) Continuing evolution in breast cancer surgical management. J Clin Oncol 23(8):1603–1606CrossRefPubMedGoogle Scholar
  32. 32.
    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):1677–1683CrossRefPubMedGoogle Scholar
  33. 33.
    Musgrove EA, Sergio CM, Loi S, Inman CK, Anderson LR, Alles MC, Pinese M, Caldon CE, Schutte J, Gardiner-Garden M et al (2008) Identification of functional networks of estrogen- and c-Myc-responsive genes and their relationship to response to tamoxifen therapy in breast cancer. PloS one 3(8):e2987CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Zsolt Gabos
    • 1
  • John Thoms
    • 1
  • Sunita Ghosh
    • 2
  • John Hanson
    • 2
  • Jean Deschênes
    • 3
  • Siham Sabri
    • 4
  • Bassam Abdulkarim
    • 1
  1. 1.Department of Radiation OncologyCross Cancer Institute and University of AlbertaEdmontonCanada
  2. 2.Department of Statistics and EpidemiologyCross Cancer Institute and University of AlbertaEdmontonCanada
  3. 3.Department of Laboratory Medicine and PathologyCross Cancer Institute and University of AlbertaEdmontonCanada
  4. 4.Department of Experimental OncologyCross Cancer Institute and University of AlbertaEdmontonCanada

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