Abstract
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.
Highlights
Triple-negative breast cancer (TNBC) shows an aggressive clinical behavior, poor clinical outcome and has limited option for targeted therapies
We investigated the influence of methylguanine-DNA-methyltransferase gene (MGMT) promoter methylation on therapy response and survival of patients with TNBC, treated with chemotherapy with and without adding of carboplatin
An increased MGMT promoter methylation has a predictive impact for increased pathological complete response (pCR) and therapy response to temozolomide [19, 20]
Summary
Triple-negative breast cancer (TNBC) shows an aggressive clinical behavior, poor clinical outcome and has limited option for targeted therapies. Due to the absence of targets, like estrogen receptor (ER), progesterone receptor (PR) and growth factor receptors (HER2), TNBC does not benefit from hormonal or anti-HER2-based therapies and therapy strategies are focused on the use of chemotherapeutic agents, for example carboplatin [1]. Alterations in epigenetics, for example methylation status of CpG islands of DNA promoter regions, were considered as early and common events in cancer and play a major role in tumor progression [2,3,4,5]. Hypermethylation of CpG islands in gene promoter regions results in loss of the target protein, lack of mRNA expression or reduced enzyme activity [7,8,9]
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