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.

Acknowledgments

The authors thank all the MARIE study participants for their contribution and the interviewers who collected the data. They thank U. Eilber and S. Behrens for excellent data management and coordination; in particular, S. Becker, K. Zaineddin, K. Buck, and M. Celik for sample preparation of baseline samples; T. Ilola (Labmaster, Finland) for biomarker measurements of baseline samples; M. Celik for sample preparation of FU1 samples; R. Owen (DKFZ, Heidelberg) for methods development for measuring FU1 samples; C. Wess (Waters GmbH, Eschborn) for biomarker measurements of FU1 samples. Last but not least, we express our deep gratitude to Dieter Flesch-Janys for his invaluable contributions to the MARIE projects throughout all these years as PI of the Hamburg study region and close collaborator.

Disclosure statement

The authors report no conflicts of interest.

Funding

The MARIE study was funded by the German Cancer Aid (Deutsche Krebshilfe e.V.; Grant numbers 70-2892-BR I, 108419 and 108253, 110826 and 110828), the German Cancer Research Center (DKFZ) and the Hamburg Cancer Society. MH was funded by the German Federal Ministry of Education and Research (Grant Number 01ER1306 PERGOLA).

Author contributions

J.C-C. conceived and designed the MARIE study; S.J. coordinated sample selection and assisted with blood sample extraction of FU1 samples; S.J. and J.C-C. performed statistical analysis, interpreted the data, and wrote the manuscript; M.H. performed landmark analyses; S.B. performed data management; A.H, S.G-M., and A.J. gave statistical support; G.P. and R.H. were responsible for the biomarker measurements; H.B. and N.O. gave scientific support; and all authors read and approved the final manuscript.