A seven-gene methylation markers panel: An epigenetic predictor of neoadjuvant chemotherapy sensitivity in triple-negative breast cancer

Abstract

Abstract Background Nowadays anthracycline and taxane-based chemotherapy remains the standard of care for TNBC, with pathological complete response (pCR) rates ranging ∼ 10–30%. pCR in TNBC is associated with better outcomes, while residual disease after neoadjuvant chemotherapy (NACT) have a higher relapse risk and poor prognosis. We have evaluated the utility of DNA methylation markers for TNBC pCR prediction. Methods Epigenetic assessment of DNA extracted from 29 biopsy samples obtained from TNBC patients prior to NACT was performed by genome-wide analysis of DNA methylation by XmaI-RRBS, and CpG dinucleotides differential methylation of which discriminates TNBC samples with different sensitivity to anthracycline and taxane-based NACT were selected. Results Based on XmaI-RRBS results we have developed a seven-gene methylation marker panel (PRKCB, PTGER2, TMEM132D, VGLL4, MYO15B, GMDS, CDO1) predicting TNBC sensitivity to NACT (cisplatin, doxorubicin, paclitaxel) with an area under the ROC curve (AUC) = 0.87 (95% CI = 0.73-1.00). The diagnostic properties of the system were estimated: specificity was 93%, sensitivity - 76% and accuracy - 0.86%. Table: 58P . Gene promoter methylation frequencies in tumors responding and not responding to anthracycline and taxane-based NACT Gene Non-responders, % Responders, % PRKCB 6.3 30.8 PTGER2 56.3 69.2 TMEM132D 87.5 92.3 VGLL4 56.3 38.5 MYO15B 81.3 76.9 GMDS 56.2 53.8 CDO1 43.8 7.7 Conclusions These results show that NACT pCR in TNBC could be accurately predicted with a seven-gene methylation markers panel. Reasonable diagnostic sensitivity and specificity values are achieved only when the markers are evaluated in complex; in separate the differences in gene methylation frequencies between responding and non-responding tumors may be negligible (Table). Further verification of these results on the validating cohort is warranted. Legal entity responsible for the study Research Centre for Medical Genetics. Funding Russian Science Foundation (project No.18-15-00430). Disclosure All authors have declared no conflicts of interest.