Postmenopausal hormone therapy and colorectal cancer risk by molecularly defined subtypes among older women

David Limsui, Robert A. Vierkant, Lori S. Tillmans, Alice H. Wang, Daniel J. Weisenberger, Peter W. Laird, Charles F. Lynch, Kristin E. Anderson, Amy J. French, Robert W. Haile, Lisa J. Harnack, John D. Potter, Susan L. Slager, Thomas C. Smyrk, Stephen N. Thibodeau, James R. Cerhan, Paul J. Limburg

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25 Scopus citations

Abstract

Background: Postmenopausal hormone (PMH) therapy may reduce colorectal cancer (CRC) risk, but existing data are inconclusive. Objectives: To evaluate associations between PMH therapy and incident CRC, overall and by molecularly defined subtypes, in the population-based Iowa Women's Health Study of older women. Methods: Exposure data were collected from Iowa Women's Health Study participants (55-69 years) at baseline (1986). Archived, paraffin-embedded tissue specimens for 553 CRC cases were collected and analysed to determine microsatellite instability (MSI-L/MSS or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive) and BRAF mutation (BRAF-wildtype or BRAF-mutated) status. Multivariable Cox regression models were fit to estimate RRs and 95% CIs. Results: PMH therapy (ever vs never use) was inversely associated with incident CRC overall (RR=0.82; 95% CI 0.72 to 0.93), with a significantly lower risk for MSI-L/MSS tumours (RR=0.75; 95% CI 0.60 to 0.94), and borderline significantly lower risks for CIMP-negative (RR=0.79; 95% CI 0.63 to 1.01) and BRAF-wildtype (RR=0.83; 95% CI 0.66 to 1.04) tumours. For PMH therapy >5 years, the subtype-specific risk estimates for MSI-L/MSS, CIMP-negative and BRAF-wildtype tumours were: RR=0.60, 95% CI 0.40 to 0.91; RR=0.68, 95% CI 0.45 to 1.03; and RR=0.70, 95% CI 0.47 to 1.05, respectively. PMH therapy was not significantly associated with the MSI-H, CIMP-positive or BRAF-mutated CRC subtypes. Conclusions: In this prospective cohort study, PMH therapy was inversely associated with distinct molecularly defined CRC subtypes, which may be related to differential effects from oestrogen and/or progestin on heterogeneous pathways of colorectal carcinogenesis.

Original languageEnglish (US)
Pages (from-to)1299-1305
Number of pages7
JournalGut
Volume61
Issue number9
DOIs
StatePublished - Sep 1 2012

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ASJC Scopus subject areas

  • Gastroenterology

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Limsui, D., Vierkant, R. A., Tillmans, L. S., Wang, A. H., Weisenberger, D. J., Laird, P. W., Lynch, C. F., Anderson, K. E., French, A. J., Haile, R. W., Harnack, L. J., Potter, J. D., Slager, S. L., Smyrk, T. C., Thibodeau, S. N., Cerhan, J. R., & Limburg, P. J. (2012). Postmenopausal hormone therapy and colorectal cancer risk by molecularly defined subtypes among older women. Gut, 61(9), 1299-1305. https://doi.org/10.1136/gutjnl-2011-300719