Genomics and proteomic analysis of breast cancer 12O MOLECULAR SUBTYPE OF BREAST CANCER METASTASES SIGNIFICANTLY INFLUENCES PATIENT POST-RELAPSE SURVIVAL

Background: We and others have previously demonstrated the propensity of standard breast cancer markers to alter their expression throughout tumor progression, with subsequent impact on patient survival. In this study our aim was to investigate tumor characteristics in metastases and their influence on post-relapse survival. Patients and methods: The Swedish multicenter trial TEX enrolled 287 patients with a morphologically confirmed loco-regional or distant breast cancer relapse from December 2002 until June 2007. The translational aspect of the trial included 120 relapse biopsies from 111 patients, yielding sufficient tumor RNA for gene expression profiling (Affymetrix array GPL10379). Each gene expression array was individually background corrected and normalized using robust multichip averaging. The gene expression modules (Desmendt et al, 2008) and the PAM50 intrinsic subtypes (Parkeret al, 2009) were assessed. Results: Gene modules showed an over-representation of aggressive relapse tumor characteristics including low ER signaling, as well as high proliferation, HER2 and angiogenic signaling. The PAM50 intrinsic breast cancer subtypes revealed that 25% of relapses were Basal, 32% HER2, 10% Luminal A, 28% Luminal B, and 5% Normal-like. Importantly, intrinsic subtype at relapse was significantly associated with post-relapse survival (log-rank P = 0.012). Contrasting two consecutive relapse biopsies from the same patient, using hierarchical clustering of gene module genes, we noted that 2 out of 7 patients exhibited different gene expression patterns, suggesting intra-tumor heterogeneity in these relapses. Conclusions: Our findings indicate that themolecular subtype of ab reast cancer relapse significantly influences post-relapse survival. Furthermore, we found relapse characteristics to be more aggressive, with an over-representation of ER-negative, HER2-positive and highly proliferative tumors, compared with the primary tumor setting. This study highlightsthat molecular investigations at relapse may provide prognostically relevant information, with the potential to improve patient management and post-relapse survival.