10511 Background: Loss of a functional DNA-damage response (DDR) sensitizes tumors to DNA-damaging as well as targeted therapeutics such as PARP-1 inhibitors. However, there is no assay to detect DDR proficiency and guide therapeutic choice. Although abrogation of the DDR can result from multiple mechanisms, including loss of components of the BRCA/Fanconi anemia pathway, the resultant DNA-damage may activate common molecular pathways. We hypothesized that these pathways could define a molecular subgroup and form the basis of a diagnostic test for sensitivity to DNA-damaging and targeted therapies.
METHODS: Using DNA-microarray technology, we profiled a cohort of BRCA mutant enriched and thus DDR-deficient (DDRD) primary breast tumor samples. Hierarchical agglomerative clustering analysis was performed and identified a molecular subtype in breast cancer characterized by activation of pathways known to respond to DNA damage. Computational classification was performed resulting in the generation of a gene signature that could identify this DDRD molecular subgroup.
RESULTS: A subset of tumors was identified as displaying biology associated with DDRD. Computational classification was performed based upon expression of this DDRD-related biology resulting in the generation of a 44-gene signature. Retrospective validation in independent breast cancer datasets indicated that the DDRD signature was predictive of response to anthracycline-based chemotherapy with an odds ratio of 15.02 (CI 3.51 - 63.49). In addition, the signature could accurately identify non-responding patients with a negative predictive value of 0.96 (CI 0.88-0.99).
CONCLUSIONS: We report the identification of a novel molecular subgroup associated with a deficiency in DDR that can be identified in both ER-positive and ER-negative breast cancer using a 44-gene signature. This subgroup is enriched for BRCA1/2 mutant tumors and demonstrates sensitivity to DNA-damaging agents. We propose that the DDRD signature could be used as a patient stratification tool for existing chemotherapy or as a clinical trial enrichment tool for DNA-damaging or repair targeted drugs in development.
|Journal||Journal of Clinical Oncology|
|Publication status||Published - 20 May 2011|