In a secondary analysis of 78,209 women from the PLCO Cancer Screening Trial, ever-use of menopausal hormone therapy (MHT) was associated with a 17% higher breast cancer incidence (aHR 1.17, 95% CI 1.10–1.24), particularly for hormone-receptor-positive subtypes. Yet the same MHT users showed 28% lower breast cancer mortality (aHR 0.72, 0.62–0.83) and 13% better overall survival. Early menopause (before age 45) was linked to lower hormone-receptor-positive incidence but not to overall breast cancer risk after adjustment. In a nested methylome subset of 1,503 women, early menopause correlated with faster epigenetic aging and shorter DNA-methylation-based telomere length — particularly among cancer cases — and these aging markers partly mediated the early-menopause breast cancer associations.
This finding lands in charged territory. Since the 2002 Women's Health Initiative alarm, MHT prescribing collapsed despite ongoing debate about net benefit. This analysis adds a critical nuance: MHT may raise incidence while simultaneously improving survival — possibly by promoting detection of less aggressive tumors or through immune-related mechanisms. The distinct methylome signature of MHT versus menopause timing suggests these exposures act through separate biological pathways, not simply as mirrors of hormonal status. Limitations include the observational design, residual confounding, and the nested methylome subset being relatively small. Crucially, this is a preprint not yet peer-reviewed, and the survival paradox warrants replication before influencing clinical guidance. Nonetheless, the mortality-incidence dissociation could meaningfully shift how clinicians counsel perimenopausal women weighing MHT.