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

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.

Associations between Environmental Exposures and Incident Colorectal Cancer by ESR2 Protein Expression Level in a Population-Based Cohort of Older Women

“…Concordantly, emerging data from our group and others demonstrate differential associations between common environmental exposures, including smoking, MHT and folate, and incident CRCs defined by microsatellite instability (MSI), CpG island methylator phenotype (CIMP), KRAS and BRAF mutation status (2–3,15–18) and TP53 protein expression (19), among other phenotypic markers. Most significantly, post-menopausal MHT was associated with a lower risk for MSI-L/MSS tumors (15) and smoking was shown to be associated with MSI-high, CIMP-positive, and BRAF-mutated tumors (2). …”

“…smoking, MHT, and folate were investigated as potentially modifiable lifestyle, medication, and dietary factors, respectively. Based on previous reports from our group and others (2–3, 15–16, 18–19), these exposures may be plausibly linked to heterogeneous pathways of colorectal carcinogenesis.…”

“…Folate was computed by multiplying the frequency response by the nutrient content of the specified portion sizes, with additional intake from supplement use included when indicated. Previous or current MHT and duration of MHT exposure were also collected, as described previously (15). Potential confounding variables acquired from the baseline questionnaire included body mass index, waist-to-hip ratio, physical activity level, alcohol consumption, age at menarche, age at menopause, oral contraceptive use, history of diabetes mellitus and daily intake of total calories, fat, sucrose, red meat, calcium, vitamin E, and methionine.…”

Colorectal Cancer Risk Associated with Hormone Use Varies by Expression of Estrogen Receptor-β

“…Three studies observed an inverse association between menopausal hormone therapy use and microsatellite stable colorectal cancer (18)(19)(20), whereas another study reported differing associations (21). Whether ESR2 expression in colorectal cancer is associated with microsatellite status remains to be clarified, as Wong and colleagues found that ESR2 isoform 1 expression was decreased in microsatellite stable colorectal cancer compared with microsatellite-unstable colorectal cancer, but no differences in expression were observed for isoform 2 and 5 (22).…”

“…Several other studies investigated the association between use of menopausal hormone therapy and risk for molecularly defined subtypes of colorectal cancer (17)(18)(19)(20)(21). Three studies observed an inverse association between menopausal hormone therapy use and microsatellite stable colorectal cancer (18)(19)(20), whereas another study reported differing associations (21).…”