Abstract 4823: Copy number gain and increased expression of BLM and FANCI is associated with sensitivity to genotoxic chemotherapy in triple negative breast and serous ovarian cancer
Authors: Nicolai J. Birkbak, Yang Li, Zhigang C. Wang, Daniel P. Silver, James D. Iglehart, Judy E. Garber, Zoltan Szallasi, Andrea L. Richardson
Journal: Cancer Research (2012)

Abstract Introduction. Genotoxic chemotherapy such as platinum salts and anthracyclines induce DNA damage and are among the most widely used anti-cancer agents. Previous molecular studies have shown that BRCA1-associated and sporadic triple-negative breast cancers (TNBC) carry high levels of genomic abnormalities, suggesting these cancers may share similar defects in DNA repair, which may make them particularly sensitive to genotoxic chemotherapy. Results. To investigate whether specific genomic aberrations may affect cancer sensitivity to cisplatin, we generated tumor DNA copy number profiles of 21 and 24 TNBC patients who received pre-operative cisplatin-based chemotherapy in two separate clinical trials. Using the GISTIC algorithm (1), we found that only a single region on chromosome 15q26 showed consistent significant differential copy number in responders versus non-responders, being preferentially lost in non-responders, but preferentially gained in responders in both trials. To see if genes on 15q26 were associated with platinum sensitivity, we acquired gene expression data from the cisplatin TNBC trial (2), and from the carboplatin-only arm of an ovarian cancer trial (3). We then performed a leave-one-out analysis, and found 9 genes significantly associated with platinum response in at least 75% of all rounds in both cohorts. These included BLM and FANCI located in the 15q26 region, both showing higher expression in sensitive tumors, and known to be involved in related DNA repair processes. To investigate if BLM and FANCI were specifically associated with genotoxic chemotherapy sensitivity, we analyzed their expression in TNBCs from three neoadjuvant trials of epirubicin alone or taxane-containing combination therapy (5, 6) and in ovarian cancers from the taxane-only treatment arm(3). In the epirubicin trial, BLM and FANCI expression was again significantly associated with increased sensitivity to therapy. In contrast, there was no association between either BLM or FANCI expression and TNBC response to the taxane-containing regimen or ovarian cancer response to single agent taxane treatment. Conclusions. These data suggest that high expression of BLM and FANCI are associated with improved response to DNA damaging agents, but not with response to other types of chemotherapeutics. Furthermore, it suggests that the patient subpopulations that respond to drugs such as anthracyclines and taxanes are not overlapping, and that it will therefore be difficult to robustly identify predictors of single agent response based on multi-drug trials. 1. Beroukhim et al. Proc Natl Acad Sci U S A. 2007;104:20007-12. 2. Silver et al. Cancer. J Clin Oncol. 2010. 3. Ahmed et al. Cancer Cell. 2007;12:514-27. 4. Li et al. Nat Med. 2010;16:214-8. 5. Hess et al. J Clin Oncol. 2006;24:4236-44. 6. Popovici et al. Breast Cancer Res. 2010;12:R5. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4823. doi:1538-7445.AM2012-4823