Breast Cancer Research and Treatment

, Volume 136, Issue 1, pp 289–293 | Cite as

Management of small HER2 overexpressing tumours

  • Arnoud Templeton
  • Alberto Ocaña
  • Boštjan Šeruga
  • Francisco Vera-Badillo
  • Lindsay Carlsson
  • Philippe Bedard
  • Eitan Amir
Brief Report


Overexpression of the human epidermal growth factor receptor 2 (HER2) is found in 10–20 % of breast cancers and is associated with a worse prognosis. Several large studies have established the addition of trastuzumab to chemotherapy as the gold standard in early breast cancer that overexpresses HER2. Little is known about the role of such adjuvant treatment in node-negative subcentimeter tumours (‘small tumours’, pT1a/b) because these patients were generally excluded from the pivotal trials. Only the BCIRG006 study published in 2011 included such tumours if high-risk features were present. Here we review the literature of small HER2-positive tumours and present a meta-analysis of retrospective studies confirming a worse outcome in terms of disease-free survival (hazard ratio 2.6, p < 0.001) and a trend for higher odds of distant recurrence at 5 years (odds ratio [OR] 2.51, p = 0.11). We discuss these findings in the light of the increased risk of grade 3 and 4 cardiac toxicity (OR 7.6, p < 0.001) and other adverse events associated with the use of trastuzumab. Such treatment may well be a valuable option in selected patients with high-risk features but physicians should exercise caution given the small absolute benefits of adjuvant chemotherapy and trastuzumab for patients with small HER2-overexpressing tumours.


Breast cancer HER2 Meta-analysis Small tumour Treatment 


Conflict of interest

Philippe Bedard declares research funding from Roche. Eitan Amir declares an advisory role with Roche. The other authors declare that they have no conflict of interest.


  1. 1.
    Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN (2005) Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23(16):3676–3685. doi: 10.1200/JCO.2005.07.032 PubMedCrossRefGoogle Scholar
  2. 2.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182PubMedCrossRefGoogle Scholar
  3. 3.
    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(4905):707–712PubMedCrossRefGoogle Scholar
  4. 4.
    Ravdin PM, Chamness GC (1995) The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: a paradigm for the development of other macromolecular markers–a review. Gene 159(1):19–27PubMedCrossRefGoogle Scholar
  5. 5.
    Curigliano G, Viale G, Bagnardi V, Fumagalli L, Locatelli M, Rotmensz N, Ghisini R, Colleoni M, Munzone E, Veronesi P, Zurrida S, Nole F, Goldhirsch A (2009) Clinical relevance of HER2 overexpression/amplification in patients with small tumor size and node-negative breast cancer. J Clin Oncol 27(34):5693–5699. doi: 10.1200/JCO.2009.22.0962 PubMedCrossRefGoogle Scholar
  6. 6.
    Gonzalez-Angulo AM, Litton JK, Broglio KR, Meric-Bernstam F, Rakkhit R, Cardoso F, Peintinger F, Hanrahan EO, Sahin A, Guray M, Larsimont D, Feoli F, Stranzl H, Buchholz TA, Valero V, Theriault R, Piccart-Gebhart M, Ravdin PM, Berry DA, Hortobagyi GN (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):5700–5706. doi: 10.1200/JCO.2009.23.2025 PubMedCrossRefGoogle Scholar
  7. 7.
    Chia S, Norris B, Speers C, Cheang M, Gilks B, Gown AM, Huntsman D, Olivotto IA, Nielsen TO, Gelmon K (2008) Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J Clin Oncol 26(35):5697–5704. doi: 10.1200/JCO.2007.15.8659 PubMedCrossRefGoogle Scholar
  8. 8.
    Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkio S, Flander M, Helle L, Ingalsuo S, Johansson K, Jaaskelainen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354(8):809–820. doi: 10.1056/NEJMoa053028 PubMedCrossRefGoogle Scholar
  9. 9.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659–1672. doi: 10.1056/NEJMoa052306 PubMedCrossRefGoogle Scholar
  10. 10.
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353(16):1673–1684. doi: 10.1056/NEJMoa052122 PubMedCrossRefGoogle Scholar
  11. 11.
    Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365(14):1273–1283. doi: 10.1056/NEJMoa0910383 PubMedCrossRefGoogle Scholar
  12. 12.
    Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sanchez Rovira P, Piccart-Gebhart MJ (2007) 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369(9555):29–36. doi: 10.1016/S0140-6736(07)60028-2 PubMedCrossRefGoogle Scholar
  13. 13.
    Spielmann M, Roche H, Delozier T, Canon JL, Romieu G, Bourgeois H, Extra JM, Serin D, Kerbrat P, Machiels JP, Lortholary A, Orfeuvre H, Campone M, Hardy-Bessard AC, Coudert B, Maerevoet M, Piot G, Kramar A, Martin AL, Penault-Llorca F (2009) Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol 27(36):6129–6134. doi: 10.1200/JCO.2009.23.0946 PubMedCrossRefGoogle Scholar
  14. 14.
    Rodrigues MJ, Wassermann J, Albiges L, Brain E, Delaloge S, Stevens D, Guinebretiere JM, Mathieu MC, Kirova Y, Guillot E, Vincent-Salomon A, Cottu PH (2010) Trastuzumab treatment in t1ab, node-negative, human epidermal growth factor receptor 2-overexpressing breast carcinomas. J Clin Oncol 28(28):e541–e542. doi: 10.1200/JCO.2010.29.7952 PubMedCrossRefGoogle Scholar
  15. 15.
    Tan-Chiu E, Yothers G, Romond E, Geyer CE Jr, Ewer M, Keefe D, Shannon RP, Swain SM, Brown A, Fehrenbacher L, Vogel VG, Seay TE, Rastogi P, Mamounas EP, Wolmark N, Bryant J (2005) Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23(31):7811–7819. doi: 10.1200/JCO.2005.02.4091 PubMedCrossRefGoogle Scholar
  16. 16.
    Viani GA, Afonso SL, Stefano EJ, De Fendi LI, Soares FV (2007) Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer 7:153. doi: 10.1186/1471-2407-7-153 PubMedCrossRefGoogle Scholar
  17. 17.
    Burstein HJ, Winer EP (2009) Refining therapy for human epidermal growth factor receptor 2-positive breast cancer: t stands for trastuzumab, tumor size, and treatment strategy. J Clin Oncol 27(34):5671–5673. doi: 10.1200/JCO.2009.24.2222 PubMedCrossRefGoogle Scholar
  18. 18.
    Joerger M, Thurlimann B, Huober J (2011) Small HER2-positive, node-negative breast cancer: who should receive systemic adjuvant treatment? Ann Oncol 22(1):17–23. doi: 10.1093/annonc/mdq304 PubMedCrossRefGoogle Scholar
  19. 19.
    Fehrenbacher L, Shiraz P, Sattavat M, Capra A, Quesenberry C, Fulton R, Habel LA (2011) T1abN0M0 HER2+invasive breast cancer recurrence: population-based cohort of 17,000+consecutive breast cancers 2000–2006 at Kaiser Permanente Northern California (KPNC). J Clin Oncol 29:551CrossRefGoogle Scholar
  20. 20.
    Adjuvant Paclitaxel and Trastuzumab for Node-Negative HER2-Positive Breast Cancer. (2012) Accessed 11 Aug 2012

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Arnoud Templeton
    • 1
  • Alberto Ocaña
    • 1
  • Boštjan Šeruga
    • 2
  • Francisco Vera-Badillo
    • 1
  • Lindsay Carlsson
    • 1
  • Philippe Bedard
    • 1
  • Eitan Amir
    • 1
  1. 1.Division of Medical Oncology and Hematology, Princess Margaret Hospital, Department of MedicineUniversity of TorontoTorontoCanada
  2. 2.Department of Medical OncologyInstitute of OncologyLjubljanaSlovenia

Personalised recommendations