Abstract PD01-06: Activation of the Insulin-Like Growth Factor Pathway Distinguishes African American from European American Patients with Triple-Negative Breast Cancer by Gene Expression Profiling
Authors: Lindner RA , Offor O , Chaves J , Lezon-Geyda K , Halligan K , Fischbach N , Shaw M , Schulz V , Harris L , Tuck DP. 
Published: April 2011

Background: Triple-negative breast cancer (TNBC) is characterized by high histologic grade, high rates of distant recurrence and a poor overall prognosis. Treatment options are limited due to the lack of specific targets such as hormone receptors or HER2 which drive other breast cancer subtypes. Epidemiological studies show a markedly higher prevalence of TNBC in young women of African ancestry. In this study we sought to identify transcriptional modules that are differentially regulated between African American (AA) and European American (EA) women. Methods: A hospital-based cohort of 130 breast cancer patients diagnosed between 1985 and 2007 was selected by an institutional pathology database (CoPath) search for invasive, triple-negative breast cancer and enriched for patients of African American ethnicity. Racial distribution 47% AA, 33% EA, 8% Hispanic and 12% other or unknown. Clinical data was extracted from the Yale and Bridgeport Hospitals Tumor Registry following IRB approval. Invasive disease was identified on H&E sections and an average of 3 tissue cores from FFPE blocks were subjected to RNA extraction using the RecoverAll Total Nucleic Acid Isolation kit (Applied Biosystems) following the manufacturer's protocol. The extracted material was hybridized to Whole Genome-DASL assays (Illumina). Statistical analysis of gene expression data was carried out using Bioconductor/R software. A set of relevant signatures was selected by enrichment analysis of modules identified by principal component analysis. Signature scores were computed as Pearson correlation between the signature vector of gene contributions and each sample's expression profile for these genes. Results: African American patients show a significantly higher activation score for a 273-gene Insulin-like Growth Factor 1 signature compared with European American patients (stage-adjusted p=0.0006). Similarly, samples from AA patients show higher scores in a BRCA 1 mutant signature defined by van ‘t Veer and colleagues in 2002 (p=0.001) and in a luminal progenitor (CD49f+EpCAM+) signature from Lim et al. (2009) (p=0.01). The Genomic Grade Index (GGI, Sotiriou et al. 2006) in samples from AA patients was also found to be significantly elevated (p=0.0007). Conclusions: Our findings indicate significant activation of the IGF pathway in AA compared to EA patients with TNBC. The 273-gene IGF signature was associated with poor differentiation and high proliferation in an independent cohort, which is in agreement with the high GGI score observed in AA patients. BRCA1 mutant-like and luminal progenitor-like properties in AA tumor samples further support this hypothesis as they both are related to basal-like histology which constitutes an aggressive subgroup of triple-negative tumors. These data suggest that African American patients may benefit from IGF pathway inhibiting drugs.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD01-06.