Background: Tumors with homologous recombination (HR) deficiency are highly sensitive to DNA double strand break (DSB) inducing agents, such as alkylating agents and poly (ADP-ribose) polymerase (PARP)-inhibitors. BRCA1 or BRCA2- mutated tumors, which are HR deficient, have characteristic DNA gains and losses that can be assessed by an array Comparative Genomic Hybridization (aCGH) classifier, one for BRCA1 mutations and one for BRCA2 mutations. We have studied these aCGH profiles together with several other HR deficiency indicators in sporadic breast cancers and we have correlated their presence to neoadjuvant chemotherapy response.
Material and Methods: A total of 163 HER2-negative pre-treatment biopsies were examined, procured from sporadic breast cancer patients scheduled to receive neoadjuvant therapy with doxorubicin and cyclophosphamide. Triple negative (TN) and estrogen receptor positive (ER+/HER2-) tumors were analyzed separately. aCGH was performed to assess BRCA1-like and BRCA2-like profiles. In addition, BRCA1 promoter methylation, BRCA1 mRNA expression and amplification of the BRCA2-inhibiting gene EMSY were analyzed. Response to neoadjuvant treatment was assessed by measuring pathological complete remission (pCR) and near pCR at the time of surgery.
Results: Inactivation of BRCA1 was frequent in TN tumors: 57% of these tumors showed a BRCA1-like profile at aCGH. BRCA 1 promoter methylation and reduced BRCA1 mRNA expression were observed in 25% and 36% of the TN tumors, respectively. The BRCA1-like aCGH profile was not clearly associated with a better neoadjuvant treatment response (58% vs. 48%, p=0.47). In ER+ tumors, a BRCA2-like aCGH profile and the amplification of the BRCA2 inhibiting gene EMSY were frequently observed (43% and 13% respectively). A BRCA2-like aCGH profile was associated with a significantly higher response rate (35% vs. 14%, p=0.014). EMSY amplification and a BRCA2-like aCGH profile occurred together in only one case, suggesting mutual exclusivity. EMSY was not associated with treatment response, questioning the role of EMSY in HR deficiency.
Conclusion: Alterations associated with BRCA1 inactivation are present in about half of the TN breast cancers, but were not predictive of chemotherapy response. In ER+/HER2- tumors, the BRCA2-like aCGH profile predicts sensitivity to DSB-inducing chemotherapy, and possibly as well to new targeted agents, such as the PARP inhibitors. After validation in independent series the aCGH classifiers may lead to a diagnostic test that could assist in neoadjuvant treatment selection.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD07-07.