Genomic and transcriptional events associated with poor clinical responses to conventional therapies

Advances on several fronts have led to increases in survival duration and to reduced mortality in patients with breast cancer. These include improved procedures for earlier detection, optimization of combined surgical and radiotherapy, and use of optimized selective estrogen receptor modifiers (SERMS) and new chemotherapeutic strategies including gene-targeted therapies. In addition, molecular stratification strategies have been developed that stratify patients according to outcome. Stratification based on measurement of expression 'signatures' have been particularly effective and seem likely to improve treatment strategies. Patients at increased risk of progressive disease can be offered standard of care chemotherapy. However, some of these patients do not respond well to these treatments and current stratification strategies provide little information to guide treatment of these patients. This study of tumors from patients treated according to standard of care identifies genomic and coordinated transcriptional aberrations – especially amplification at 11q, and 20q in tumors with the luminal A expression phenotype, and at 17q in tumors associated with the ERBB2 expression phenotype – that are strongly associated with poor response to such treatment. Our study identifies genes in these regions of amplification that can be assessed to identify patients that will respond poorly to the current standard of care and that are targets for therapies that will be effective against these poorly responding tumors. Interesting, this study also shows that patients with basal-like tumors do not have substantially shorter survival durations than patients with luminal-like tumors, suggesting that basal-like tumors respond well to the adjuvant adriamycin and cyclophosphamide therapies employed during their treatment.