Identification of a low risk subgroup in Her2-positive breast cancer by the 70-gene prognosis signature.
Authors: M Knauer, F Cardoso, S Mook, P Bedard, R Koornstra, M Kok, J Bueno-de-Mesquita, J Wesseling, M van de Vijver, S Linn, E Rutgers, L van 't Veer
Journal: Cancer Research (2009)

Abstract Abstract #4171 Introduction:&amp;#x2028; Her2/neu-overexpression is observed in 15-20% of invasive breast cancers and considered a negative prognostic factor. Most Her2-positive patients are classified as high risk by current treatment guidelines and thus allocated to adjuvant trastuzumab and chemotherapy. However, 74% of patients remained distant recurrence-free at 3 years without trastuzumab in the HERA-trial (HERceptin Adjuvant). In the present study the 70-gene prognosis signature (MammaPrint™), validated as an independent prognostic indicator for patients with up to three positive lymph nodes, was used to identify a subgroup of patients with low risk and favorable outcome.&amp;#x2028; Methods:&amp;#x2028; One-hundred-sixty-nine patients with Her2-positive breast cancer were selected from a pooled dataset of 1280 patients with known Her2-status. Patients had a unilateral T1-3, N0-1 tumor and were treated with either breast-conserving therapy or mastectomy. Samples were analyzed and classified by the 70-gene signature as good or poor prognosis by Agendia Laboratories.&amp;#x2028; Results:&amp;#x2028; After a median follow-up of 65 months (range 4-303) 49 (29%) distant recurrences and 41 (24%) breast cancer-specific deaths occurred. The 70-gene signature classified 27 (16%) patients as good prognosis, with a 10-year distant disease-free survival (DDFS) of 89% (25/27), compared to 142 (84%) patients classified as poor prognosis, who had a DDFS of 64%. The estimated hazard ratios (HR) for genomic risk were 4.9 (95%CI 1.2-20.1,p=0.029) and 4.4 (95%CI 1.1-18.4,p=0.040) for DDFS and breast cancer-specific survival at 10 years, respectively. In multivariate analysis, adjusted for known prognostic factors and adjuvant therapy, only the 70-gene signature and tumor size were independent predictors for 10-year-DDFS with HRs of 5.4 (95%CI 1.3-23.4,p=0.024) and 1.05 (95%CI 1.02-1.08,p=0.001), respectively. The good prognosis group had positive hormone-receptors in 85%, and fewer patients received adjuvant therapy: 16 patients (59%) received no adjuvant treatment, 6 (22%) received adjuvant chemotherapy, 8 (30%) hormonal therapy and 1 (4%) received trastuzumab. For the subgroup of 90 patients who were not treated with adjuvant chemotherapy or trastuzumab, the HR for low versus high 70-gene signature for 10-year DDFS was 4.75 (1.13-19.92,p=0.033).&amp;#x2028; Discussion:&amp;#x2028; The 70-gene signature is a strong independent prognostic indicator that can identify a subgroup with good clinical outcome in Her2-positive early breast cancer even in the absence of adjuvant chemotherapy and trastuzumab. This subgroup will be further studied in the ongoing MINDACT-trial (MIcroarray for Node-negative and 1-3 positive node Disease may Avoid ChemoTherapy) and beyond. The MINDACT-trial will prospectively evaluate if it is acceptable to withhold chemotherapy and/or trastuzumab in Her2-positive, genomic low risk patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4171.