Abstract P3-05-01: Molecular subtyping improves stratification of patients into diagnostically more meaningful risk groups
Authors: Cristofanilli M , Turk M , Kaul K , Weaver J , Wesseling J , Stork-Sloots L , de Snoo F , Yao K 
Published: August 2014

Background: Microarray-based gene expression profiling demonstrated that breast cancer is a heterogeneous group of different diseases characterized by distinct molecular aberrations, rather than one disease. Improved understanding of the molecular phenotypes of the disease has already shown prognostic and predictive value and, when prospectively applied, could have dramatic implications in establishing a more personalized approach to the management of early-stage breast cancer. Combined use of MammaPrint and a molecular subtyping profile (BluePrint) identifies disease subgroups with marked differences in long-term outcome and response to neo-adjuvant therapy [Glück et al. ASCO 2012]. The aim of this study was to evaluate the implication of accurate molecular subtyping using MammaPrint and BluePrint in women with early-stage breast cancer treated at US Institutions following National Comprehensive Cancer Network (NCCN) standard guidelines.

Methods: 208 frozen tumor samples from consecutive BC patients (TI-III, N0-Ib) were obtained from 2 US centers. Median age at diagnosis was 56 years (range 28–89 years). Between 1992 and 2010 patients were treated either with breast-conserving therapy or mastectomy with axillary lymph node dissection followed by systemic adjuvant therapy when indicated. Sixty-three percent of patients received adjuvant endocrine therapy (ET), 58% received adjuvant chemotherapy (CT) and 32% received both. Hormone Receptor (HR) and HER2 status were assessed by immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH), following standard guidelines. Median follow-up was 11.3 years. Survival was assessed for patient groups according to local pathological assessment and compared with molecular classification of patients (centrally assessed full genome expression at Agendia laboratory).

Results: Standard HR and HER2 status assessment revealed that 57% of all tumors examined were luminal-like (ER/PR positive, HER2 negative), 20% HER2 positive and 24% triple negative. Molecular classification demonstrated discordance in the following clinical groups: 16 out of 41 patients previously identified as HER2 positive were reclassified as Luminal-type, with 97% 5-year distant metastases-free survival (DMFS) for Luminal A (MammaPrint Low Risk/Luminal-type) and 98% for Luminal B (MammaPrint High Risk/Luminal-type). Ten patients identified with clinical triple-negative tumors were reclassified with molecular subtyping as HER2 positive (n = 6) and Luminal-type (n = 4). Of the patients classified with BluePrint Basal-type tumors, 58 (28%) had a 5-year DMFS of 82% (81% received adjuvant CT). Of those with HER2-type tumors, 25 (12%) had a 5-year DMFS of 76% (88% received adjuvant CT without trastuzumab). Discordant cases are being centrally re-assessed for ER, PR and HER2.

Conclusions: This retrospective study showed that Molecular Subtyping with BluePrint and MammaPrint leads to clinically significant prognostic and molecular stratification. The use of MammaPrint and BluePrint in the management of patients with primary breast cancer should be considered for a more accurate selection of adjuvant therapies in this era of personalized medicine.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-05-01.