Departments of Experimental Therapy; Pathology, The Netherlands Cancer Institute.
Departments of Experimental Therapy.
Ann Oncol. 2011 Apr;22(4):870-876. doi: 10.1093/annonc/mdq468. Epub 2010 Oct 11.
Tumors with homologous recombination deficiency (HRD), such as BRCA1-associated breast cancers, are not able to reliably repair DNA double-strand breaks (DSBs) and are therefore highly sensitive to both DSB-inducing chemotherapy and poly (ADP-ribose) polymerase inhibitors. We have studied markers that may indicate the presence of HRD in HER2-negative breast cancers and related them to neoadjuvant chemotherapy response.
Array comparative genomic hybridization (aCGH), BRCA1 promoter methylation, BRCA1 messenger RNA (mRNA) expression and EMSY amplification were assessed in 163 HER2-negative pretreatment biopsies from patients scheduled for neoadjuvant chemotherapy.
Features of BRCA1 dysfunction were frequent in triple-negative (TN) tumors: a BRCA1-like aCGH pattern, promoter methylation and reduced mRNA expression were observed in, respectively, 57%, 25% and 36% of the TN tumors. In ER+ tumors, a BRCA2-like aCGH pattern and the amplification of the BRCA2 inhibiting gene EMSY were frequently observed (43% and 13%, respectively) and this BRCA2-like profile was associated with a better response to neoadjuvant chemotherapy.
Abnormalities 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, a BRCA2-like aCGH pattern was predictive of chemotherapy response. These findings should be confirmed in independent series.
同源重组缺陷（HRD）肿瘤，如 BRCA1 相关的乳腺癌，无法可靠地修复 DNA 双链断裂（DSBs），因此对 DSB 诱导的化疗和聚（ADP-核糖）聚合酶抑制剂高度敏感。我们研究了可能表明 HER2 阴性乳腺癌中存在 HRD 的标志物，并将其与新辅助化疗反应相关联。
在 163 例计划接受新辅助化疗的 HER2 阴性预处理活检中评估了 array 比较基因组杂交（aCGH）、BRCA1 启动子甲基化、BRCA1 信使 RNA（mRNA）表达和 EMSY 扩增。
BRCA1 功能障碍的特征在三阴性（TN）肿瘤中很常见：BRCA1 样 aCGH 模式、启动子甲基化和 mRNA 表达降低分别在 57%、25%和 36%的 TN 肿瘤中观察到。在 ER+肿瘤中，经常观察到 BRCA2 样 aCGH 模式和 BRCA2 抑制基因 EMSY 的扩增（分别为 43%和 13%），并且这种 BRCA2 样图谱与新辅助化疗的更好反应相关。
与 BRCA1 失活相关的异常存在于约一半的 TN 乳腺癌中，但不能预测化疗反应。在 ER+/HER2-肿瘤中，BRCA2 样 aCGH 模式可预测化疗反应。这些发现应在独立系列中得到证实。
