Institut für Pathologie, Philipps-Univeristät Marburg, Marburg, Germany.
Institut für Neuropathologie, Charité -Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institut of Health, Berlin, Germany.
PLoS One. 2020 Aug 25;15(8):e0238021. doi: 10.1371/journal.pone.0238021. eCollection 2020.
Triple-negative breast cancer (TNBC) is typically treated with chemotherapeutic agents, including carboplatin (Cb), an DNA platinating agent. The O6-methylguanine-DNA-methyltransferase gene (MGMT) encodes for the protein O6-alkylguanine-DNA-alkyltransferase (MGMT protein). MGMT protein is involved in DNA repair mechanisms to remove mutagenic and cytotoxic adducts from O6-guanine in DNA. In glioblastoma multiforme, MGMT methylation status is a predictive biomarker for increased response to temozolomide therapy. It has been suggested, that MGMT protein may have relevance for cellular adaptation and could have an influence on resistance to carboplatin therapy. We investigated the influence of MGMT promoter methylation on pathologic complete response and survival of patients with TNBC treated in the neoadjuvant GeparSixto trial. In 174 of 210 available TNBC tumors a valid MGMT promoter methylation status was determined by pyrosequencing of 5 CpG islands. In 21.8%, we detected a mean MGMT promoter methylation >10%. Overall, MGMT promoter methylation was not significantly associated with pathological complete response (pCR) rate. After stratification for the two therapy arms with and without Cb no statistically significant differences in therapy response rates between the two MGMT promoter methylation groups could be observed. Our results show that different MGMT promoter methylation status is not related to different chemotherapy response rates in the TNBC setting in GeparSixto.
三阴性乳腺癌（TNBC）通常采用化疗药物治疗，包括卡铂（Cb），一种 DNA 烷化剂。O6-甲基鸟嘌呤-DNA-甲基转移酶基因（MGMT）编码 O6-烷基鸟嘌呤-DNA-烷基转移酶（MGMT 蛋白）。MGMT 蛋白参与 DNA 修复机制，以去除 DNA 中 O6-鸟嘌呤上的诱变和细胞毒性加合物。在多形性胶质母细胞瘤中，MGMT 甲基化状态是对替莫唑胺治疗反应增加的预测性生物标志物。有人认为，MGMT 蛋白可能与细胞适应有关，并可能对卡铂治疗的耐药性产生影响。我们研究了 MGMT 启动子甲基化对接受新辅助 GeparSixto 试验治疗的 TNBC 患者病理完全缓解和生存的影响。在 210 个可用于分析的 TNBC 肿瘤中，通过对 5 个 CpG 岛的焦磷酸测序确定了 174 个有效 MGMT 启动子甲基化状态。在 21.8%的病例中，我们检测到平均 MGMT 启动子甲基化 >10%。总体而言，MGMT 启动子甲基化与病理完全缓解（pCR）率无显著相关性。在对含有或不含有 Cb 的两个治疗臂进行分层后，两个 MGMT 启动子甲基化组之间的治疗反应率没有观察到统计学上的显著差异。我们的结果表明，在 GeparSixto 中，不同的 MGMT 启动子甲基化状态与 TNBC 中不同的化疗反应率无关。
