Prolonged S-adenosylmethionine exposure is associated with poorer treatment response and adverse outcomes in breast cancer: a retrospective cohort study

Abstract Background Hepatoprotective regimens are frequently used during chemotherapy for breast cancer, but their effects on oncologic outcomes remain unclear. S-adenosylmethionine (SAMe), a universal methyl donor, may influence treatment response through epigenetic and epitranscriptomic regulations. Methods We retrospectively analyzed data from 1013 consecutive women with primary breast cancer treated at Zhengzhou University People’s Hospital between January 1, 2018 and January 1, 2020, and who underwent surgery followed by standard adjuvant chemotherapy. Overall survival (OS) and disease-free survival (DFS) were compared across hepatoprotective regimens. Propensity score matching (1:2) was performed to balance baseline characteristics between SAMe-treated and untreated patients. Receiver operating characteristic (ROC) analysis identified the optimal exposure threshold for recurrence discrimination, and survival was further assessed according to SAMe exposure duration using Cox proportional hazards models. Transcriptomic data from the Cancer Transcriptome Relationships Database (CTR-DB) were analyzed for SAMe-related pathways. In an exploratory neoadjuvant cohort (n = 62), intratumoral SAMe levels, m6A/m5C/m7G signals and METTL3/METTL14 expression were quantified in post-treatment tumor tissues. Results SAMe exposure during adjuvant chemotherapy was associated with shorter OS and DFS than other or no hepatoprotectants (both P < 0.05). After matching, prolonged SAMe exposure (≥ 14days) remained associated with worse OS and DFS than non-SAMe exposure (both P < 0.05), and this association persisted after multivariable adjustment. CTR-DB analyses revealed enrichment of methionine metabolism and RNA methylation-related pathways in non-responsive tumours. In the neoadjuvant cohort, tumours from patients with poor radiologic response showed higher intratumoral SAMe levels, stronger m6A signals, and higher METTL3 and METTL14 expression. Higher m6A levels were also associated with poorer MRI-based response. Conclusions Prolonged SAMe exposure during chemotherapy was associated with poorer treatment response and worse survival. Transcriptomic and tissue-level findings further support a possible link with altered m6A methylation. These results indicate that a cautious and standardized approach to SAMe use during chemotherapy may help limit treatment resistance and improve long-term outcomes.