BRCA1 gene expression signature predicts for anthracycline-chemosensitivity in triple-negative breast cancer. (2009)

Abstract Abstract #6039 Background: We used a previously published gene expression signature that can identify tumors from BRCA1 mutation carriers to evaluate its predictive value in triple-negative breast cancer as a marker for chemosensitivity to anthracycline-based chemotherapy. We proposed that based on preclinical evidence suggesting that BRCA1-deficient breast cancer cells are sensitive to DNA damaging drugs such as cisplatin and anthracyclines this gene expression profile may identify tumors with anthracycline chemosensitivity. Two previously published studies defined a gene expression signature associated with BRCA1 germline mutation.(1,2) In these studies, sporadic tumors were misclassified as BRCA1 tumors and further analysis revealed methylation of the BRCA1 promoter region and decreased BRCA1 gene expression. This finding suggests the possibility of identifying sporadic tumors with decreased BRCA1 activity.&#x2028; Methods: We selected from our database of a locally advanced breast cancer neoadjuvant trial all cases of triple negative breast cancer that received 4 cycles of doxorubicin/cyclophosphamide(AC, 60/200 mg/m2, every 3 weeks) prior to surgery. Pathologic response to chemotherapy was disappearance of all invasive cancer or microscopic residual disease. Tumoral gene expression profile previously obtained using Affymetrix U133A Chip was analyzed for an optimal set of 100 most differentially expressed genes distinguishing BRCA1 and sporadic triple negative tumors according to the previously identified gene signature by van't Veer et al.1 We performed unsupervised clustering to determine if this signature could classify a subtype of triple-negative tumors with "BRCAness" and to test our hypothesis that BRCA1-like tumors are more sensitive to AC. We then performed a supervised analysis to determine the most differentially expressed genes that could prospectively identify triple-negative sporadic tumors with “BRCAness” and tumors from BRCA1 germline carriers that are sensitive to anthracyclines.&#x2028; Results: Of the 66 patients enrolled in our neoadjuvant trial, 12 patient's tumors were triple negative and received preoperative AC. By unsupervised clustering, the gene expression pattern associated with BRCA1 cancers subdivided these sporadic cancers in to two groups: Group A(6/7 pathologic responders), and group B(5/5 non-pathologic responders). By supervised analysis, the most differentially overexpressed gene from the BRCA1 profile for AC sensitivity was YWHAH(14-3-3 eta polypeptide), while DKK3(Inhibitor of Wnt and Notch signaling pathway) and RPL23A were most overexpressed in all cases with adriamycin-resistance(p&lt;0.01).&#x2028; Discussion: Triple negative sporadic breast cancer displaying “BRCAness” appear to be sensitive to AC chemotherapy. YWHAH, DKK3, and RPL23A are differentially expressed in anthracycline-sensitive versus resistant tumors. These three genes can potentially identify triple-negative breast cancers that exhibit “BRCAness” and sensitivity to DNA-damaging chemotherapy such as cisplatin, anthracycline, or PARP inhibitors. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6039.