10536 Background: While HER2 status is used prognostically, the effects of HER2 can be influenced by other genes; co- amplification of TOP2A modulates the effectiveness of treatment with Herceptin. BRCA1, deleted in >50% of sporadic breast tumors, is located distal to HER2 on chromosome 17q and is marked by structural instability. To determine how alterations at the BRCA1 locus may modify amplification of HER2, FISH analysis of BRCA1 was performed in breast tumors with HER2 amplification and/or allelic imbalance on chromosome 17q12. Methods: HER2 status (n=68) was determined using the PathVysion HER2 kit. For BRCA1 analysis, DNA probes were generated by nick translation from a BAC clone containing the entire BRCA1 gene in conjunction with a CEP 17 probe. Copy number gains and deletions were defined as BRCA1:CEP17 >1.3 and <0.8, respectively; aneusomy was defined when >10% of tumor cells had copy numbers > (polysomy) or < (monosomy) than two. Results: Amplification of the HER2 gene was detected in 57% of tumors; an additional 16% of tumor were polysomic for chromosome 17q. The remaining 27% of tumors had previously detected allelic imbalance at the 17q12 region. The majority of samples (47%) were characterized by an amplification of HER2 with a downstream deletion of BRCA1, while HER2 and BRCA1 were amplified concomitantly in 21% of tumors, including those with polysomy of 17q. Fifteen percent of samples were monosomic for chromosome 17q; using current clinical scoring criteria, each of those samples were reported as having, despite the altered copy number, negative HER2 status. Levels of overall genomic instability, which were previously measured at 26 chromosomal regions, were significantly higher (P<0.05) in tumors with deletion of BRCA1 compared to those without loss of BRCA1 (38% and 24%, respectively). Conclusions: Alterations, especially deletions, of BRCA1 are highly correlated with copy number changes in HER2. Because deletion of BRCA1 has been associated with overall genomic instability, patients with amplification of HER2 and deletion of BRCA1 may prove unresponsive treatment with Herceptin. Loss of BRCA1 should, therefore, be considered as a genetic modifier to HER2 amplification and the status of BRCA1 should be considered in selecting treatment options for patients with HER2 amplified tumors. No significant financial relationships to disclose.
High-density SNP arrays improve detection of HER2 amplification and polyploidy in breast tumors
