A translational research project evaluating the MGMT promoter methylation status in TNBC from GeparSixto has been published in PLoSOne
Triple-negative breast cancer (TNBC) is typically treated with chemotherapeutic agents, including carboplatin, an DNA platinating agent. 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. The O6-methylguanine-DNA-methyltransferase gene (MGMT) is involved in DNA repair mechanisms to remove mutagenic and cytotoxic adducts from O6-guanine in DNA. It has been suggested, that MGMT protein may have relevance for cellular adaptation and could have an influence on resistance to carboplatin therapy. It has also been shown that pCR rates after neoadjuvant cisplatin therapy correlated with downregulation of DNA repair enzymes, such as MGMT protein, in BRCA1-associated TNBC. This study investigated the influence of MGMT promoter methylation on pathologic complete response (pCR) and survival of patients with TNBC treated in the neoadjuvant GeparSixto trial.
The MGMT promoter methylation status was assessed by methylation-specific polymerase-chain reaction (PCR) and subsequent pyrosequencing of 5 CpG islands. For each CpG island the percentage of methylation was measured and a mean percentage of methylation across all CpG islands was calculated for each tumor sample. MGMT methylation was defined as positive if this mean value was >10%.
In 174 of 210 available TNBC tumors from GeparSixto study, MGMT promoter methylation status was assessed and in 21.8%, a MGMT promoter methylation >10% was detected. According to treatment arms, 24.3% of patients in the carboplatin arm and 19.4% of patients in the non-carboplatin arm had a methylated MGMT promoter region. Regarding the number of methylated CpG islands in the MGMT promoter, none or two CpG islands were methylated. Patients in the non-carboplatin arm had more often 2 of 5 methylated CpG island compared to the cohort with carboplatin. Overall, MGMT promoter methylation was not significantly associated with pCR rate. Similar results were obtained according to treatment arm and BRCA mutation status. In the carboplatin arm, BRCA mutated tumors had pCR rates of 84.6% for unmethylated MGMT and 80.0% for methylated MGMT whereas the pCR rates for BRCA wildtype patients were 57.5% for unmethylated MGMT and 50.0% for methylated MGMT. In the non-carboplatin arm, BRCA mutated patients had pCR rates of 40.0% for unmethylated MGMT and 50.0% for methylated MGMT subgroup while the pCR rates for BRCA wildtype tumors were 27.1% for unmethylated MGMT and 25.0% for methylated MGMT subgroup.
These results demonstrated that MGMT promoter methylation has no direct impact on response to neoadjuvant chemotherapy with or without the addition of carboplatin in the TNBC cohort from GeparSixto trial.
Jank P, Gehlhaar C, Bianca L, et al. MGMT promoter methylation in triple negative breast cancer of the GeparSixto trial. PLoS One. 2020;15:e0238021.