Abstract PD01-04: Histological Features of ER-Low, HER2-Negative Breast Cancer Predict Response to High Dose, Platinum-Based Chemotherapy
Authors: Wesseling J , Vollebergh MA , Hauptmann M , Wessels LF , Nederlof PM , de Vries EG , Rodenhuis S , van de Vijver MJ , Linn SC. 
Published: April 2011

Abstract
Background: Breast cancer cells deficient for BRCA1 are hypersensitive to agents eventually resulting in double-strand DNA breaks, such as platinating agents and poly(ADP-ribose)polymerase (PARP)-inhibitors. Using a BRCA1 array comparative genomic hybridization (aCGH) classifier, we previously identified BRCA1-like tumors with a functional BRCA1-loss, caused by BRCA1-mutation, BRCA1-promoter methylation, or an as yet unidentified mechanism. We observed that these BRCA1- like(CGH) tumors showed an expansive growth pattern, one of the histological features of BRCA1-mutated breast cancer. The aim of this study was to determine which combination of histological features associated with BRCA1-mutated breast cancer were present in the BRCA1-like(CGH) subtype and might predict sensitivity to platinating chemotherapy. Methods: We studied histological features, which are known to be associated with BRCA1-mutations in literature: growth pattern, necrosis, lymphocytic infiltrate and mitotic count. In an independent series of metastatic breast cancer patients (MBC, n=39) for which BRCA1- like(CGH) status was known, whole slides were scored for all features. Features were first tested for significant association with BRCA1- like(CGH) status. Next, significantly associated features were tried in different combinations to find the highest sensitivity to predict for BRCA1- like(CGH) status (BRCA1-histological combination). This histological combination was subsequently tested in stage-III estrogen-receptor low, HER2-negative breast cancer patients, who had been randomized between adjuvant high-dose (HD) platinum-based alkylating chemotherapy and conventional chemotherapy. Additionally, we assessed the association of BRCA1-like(aCGH) status and BRCA1-loss through mutation or promoter methylation with the histological combination in a random subgroup. Results: The combination of a ‘mitotic count above 19 per 2 mm2 with either ‘an expansive growth pattern’ or ‘necrosis’ correctly identified the BRCA1-like(CGH) tumors with a sensitivity of 88% and a specificity of 86% in the MBC patients. In the adjuvant stage-III series, greater benefit was observed from HD-platinum-based chemotherapy versus conventional chemotherapy among patients with the BRCA1-histological combination (41/136=30%, multivariate HR=0.20, 95%CI 0.07-0.62; 7-year recurrence free survival (RFS) 78% versus 39%), compared to patients with other histological features (95/136=70%, HR=0.53, 95%CI 0.29-0.95, 7-year RFS 55% versus 43%), although without a significant difference (test for interaction p=0.14). Analyses of patients with tumors with a mitotic count above 19 only, showed similar results for the BRCA1-histological combination (in this subgroup: expansive growth or necrosis, p-interaction: 0.07). The BRCA1-histological combination was significantly associated with BRCA1-like(CGH) status and BRCA1-mutations, but not with BRCA1-promoter methylation.
Conclusion: Using histology only, we were able to identify a large proportion of the aCGH defined BRCA1 molecular subtype. Here, we present the first data that histology might be a biomarker for identifying high-risk patients benefiting from platinum-based chemotherapy in the absence of molecular-based techniques.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD01-04.