Prognostic associations of circulating phytoestrogens and biomarker changes in long-term survivors of postmenopausal breast cancer

Abstract Lignans are associated with improved postmenopausal breast cancer (BC) survival, but whether these associations, particularly with enterolactone (major lignan metabolite), persist over time is unclear. Little is known about other phytoestrogens on prognosis in long-term survivors. The study examines associations of prognosis with 1) circulating postdiagnosis enterolactone, 2) eight circulating phytoestrogen metabolites, and 3) changes in enterolactone and genistein. In a German cohort of 2,105 postmenopausal BC patients with blood samples collected at recruitment 2002–2005 (baseline) and re-interview in 2009 (follow-up), delay-entry Cox proportional hazards regression was used. Landmark analysis showed that circulating enterolactone (log2) associations with 5-year survival changed over time, with strongest hazard ratios of 0.89 (95% CI, 0.80–0.99) at blood draw (BD) and 0.86 (0.77–0.97) at 2 years post-BD for BC mortality, and 0.87 (0.80–0.95) at BD and 0.84 (0.76–0.92) at 3 years post-BD for all-cause mortality, which attenuated thereafter. In long-term survivors, increasing concentrations of genistein (1.17, 1.01–1.36), resveratrol (1.19, 1.02–1.40), and luteolin (1.96, 1.07–3.58) measured in follow-up blood samples were associated with poorer subsequent prognosis. Neither enterolactone at follow-up nor changes in enterolactone/genistein were associated with prognosis. Large long-term longitudinal studies with multiple phytoestrogen measurements are required to understand long-term effects of phytoestrogens after BC.