Role of HER2-neu as a prognostic factor for survival and relapse in pT1a–bN0M0 breast cancer: a systematic review of the literature with a pooled-analysis
First Online: 14 March 2012 Received: 16 January 2012 Accepted: 23 February 2012 DOI:
10.1007/s12032-012-0201-4 Cite this article as: Petrelli, F. & Barni, S. Med Oncol (2012) 29: 2586. doi:10.1007/s12032-012-0201-4 Abstract
High levels of human epidermal growth receptor 2 (HER2) expression are associated with recurrence and death in breast cancer (BC) patients. We have performed a systematic review and meta-analysis in order to evaluate the prognosis for HER2+ pT1a–bN0M0 BC patients. A search of PubMed and Embase was performed. Studies were included if they reported hazard ratios (HRs) with a 95% confidence interval (CI) for multivariate analyses of relapse or survival in pT1a–bN0M0, HER2+ BC patients treated with surgery and chemotherapy and/or endocrine therapy, but not with trastuzumab. A total of 764 patients from seven studies were included in the meta-analysis. In the pooled analysis, HER2 had a detrimental effect on relapse-free (HR 4.68, 95% CI 3.05–7.18;
p < 0.00001) and distant relapse-free survival, with a HR of 5.6 (95% CI 2.65–11.85; p < 0.00001). HER2+ status was also linked to increased risk of death (HR 3.4, 95% CI 0.86–13.41; p = 0.08) and worst BC-specific survival (HR 2.61, 95% CI 1.51–4.51; p = 0.0006), but these data were presented in few studies. HER2+ pT1a–bN0M0 BC is associated with a dismal prognosis. In these patients, HER2 has to be taken into account when deciding on adjuvant therapy, and trastuzumab should be considered. Keywords pT1a–bN0M0 HER2 positive Breast cancer Relapse Survival Prognosis References
Chia SK, Speers CH, Bryce CJ, Hayes MM, Olivotto IA. Ten-year outcomes in a population-based cohort of node-negative, lymphatic, and vascular invasion-negative early breast cancers without adjuvant systemic therapies. J Clin Oncol. 2004;22(9):1630–7.
Hanrahan EO, Valero V, Gonzalez-Angulo AM, Hortobagyi GN. Prognosis and management of patients with node-negative invasive breast carcinoma that is 1 cm or smaller in size (stage 1; T1a, bN0M0): a review of the literature. J Clin Oncol. 2006;24(13):2113–22.
Press MF, Bernstein L, Thomas PA, et al. Her-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol. 1997;15(8):2894–904.
Joensuu H, Isola J, Lundin M, et al. Amplification of erbB2 and erbB2 expression are superior to estrogen receptor status as risk factors for distant recurrence in pT1N0M0 breast cancer: a nationwide population-based study. Clin Cancer Res. 2003;9(3):223–30.
Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009;27(34):5685–92.
Gianni L, Dafni U, Gelber RD, et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011;12(3):236–44.
Ramond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable Her 2-positive breast cancer. N Engl J Med. 2005;353:1673–84.
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273–83.
Higgins JPT, Green S (eds). Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated Mar 2011]. The Cochrane collaboration. 2011. Available from
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.
Livi L, Meattini I, Saieva C, et al. Prognostic value of positive human epidermal growth factor receptor 2 status and negative hormone status in patients with T1a/T1b, lymph node-negative breast cancer. Cancer. 2011; in press.
Cancello G, Maisonneuve P, Rotmensz N, et al. Prognosis in women with small (T1mic, T1a, T1b) node-negative operable breast cancer by immunohistochemically selected subtypes. Breast Cancer Res Treat. 2011;127(3):713–20.
Sanpaolo P, Barbieri V, Pedicini P, Fusco V. Her-2 prognostic value in very early-stage breast cancer: a single-institution retrospective analysis. Med Oncol. 2011. doi:
Park YH, Kim ST, Cho EY, et al. A risk stratification by hormonal receptors (ER, PgR) and HER-2 status in small (≤1 cm) invasive breast cancer: who might be possible candidates for adjuvant treatment? Breast Cancer Res Treat. 2010;119(3):653–61.
Curigliano G, Viale G, Bagnardi V, et al. Clinical relevance of HER2 overexpression/amplification in patients with small tumor size and node-negative breast cancer. J Clin Oncol. 2009;27(34):5693–9.
Theriault RL, Litton JK, Mittendorf EA, et al. Age and survival estimates in patients who have node-negative T1ab breast cancer by breast cancer subtype. Clin Breast Cancer. 2011;11(5):325–31.
Wong F, Tuan J, Chua ET. Her2-neu positivity prognosticates for poor disease control in Asian women with small, node negative breast cancer treated with conservation therapy. Int J Radiat Oncol Biol Phys. 2010;78(3 suppl 1):S228.
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.
Paik S, Hazan R, Fisher ER, et al. Pathologic findings from the national surgical adjuvant breast and bowel project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J Clin Oncol. 1990;8:103.
van de Vijver MJ, Mooi WJ, Wisman P, et al. Immunohistochemical detection of the neu protein in tissue sections of human breast tumors with amplified neu DNA. Oncogene. 1988;2:175.
Gilcrease MZ, Woodward WA, Nicolas MM, et al. Even low-level HER2 expression may be associated with worse outcome in node-positive breast cancer. Am J Surg Pathol. 2009;33:759.
Taucher S, Rudas M, Mader RM, et al. Do we need HER-2/neu testing for all patients with primary breast carcinoma? Cancer. 2003;98:2547.
Tandon AK, Clark GM, Chamness GC, et al. HER-2/neu oncogene protein and prognosis in breast cancer. J Clin Oncol. 1989;7:1120.
Gusterson BA, Gelber RD, Goldhirsch A, et al. Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) breast cancer study group. J Clin Oncol. 1992;10:1049.
Pauletti G, Dandekar S, Rong H, et al. Assessment of methods for tissue-based detection of the HER-2/neu alteration in human breast cancer: a direct comparison of fluorescence in situ hybridization and immunohistochemistry. J Clin Oncol. 2000;18:3651.
Kröger N, Milde-Langosch K, Riethdorf S, et al. Prognostic and predictive effects of immunohistochemical factors in high-risk primary breast cancer patients. Clin Cancer Res. 2006;12:159.
Chia S, Norris B, Speers C, et al. 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. 2008;26:5697.
Wiechmann L, Jacks L, Patil S, et al. Impact of molecular subtype on presenting characteristics of T1a, b tumors. J Clin Oncol. 2009; 27:15s (abstr 11111).
Rodrigues MJ, Wassermann J, Albiges-Sauvin L, et al. Treatment of node-negative infracentimetric HER2+ invasive breast carcinomas: a joint AERIO/REMAGUS study. J Clin Oncol. 2009;27:15s (abstr 517).
Wassermann J, Albiges L, Rodrigues MJ, et al. Treatment of small node-negative HER2+ invasive breast carcinomas: 40-month update of the joint Aerio/Remagus study. J Clin Oncol. 2011;29:85–96 (abstr 557).
Chew HK, Brown M. Cause-specific and all-cause mortality of HER2-positive, node-negative, T1a and T1b breast cancers. J Clin Oncol. 2010;28:15s (abstr 583).
Kwon JH, Kim YJ, Lee KW, et al. Triple negativity and young age as prognostic factors in lymph node-negative invasive ductal carcinoma of 1 cm or less. BMC Cancer. 2010;10:557.
Wong FY, Yip CS, Chua ET. Implications of HER2 Amplification in small, node-negative breast cancers: do Asians differ? World J Surg. 2011;36(2):287–94.
Parise C, Bauer K, Caggiano V. Is tumor size important in HER2-positive breast cancer? J Clin Oncol. 2010;28:15s (abstr 1582).
National Comprehensive Cancer Network (NCCN) guidelines. Available at:
(accessed on 12 Nov 2011).
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