Postmenopausal Hormone Therapy and Colorectal Cancer Risk in Relation to Somatic KRAS Mutation Status among Older Women
Cette étude de cohorte en population américaine incluant 41 836 femmes âgées de 55 à 69 ans évalue les interactions entre l'utilisation d'un traitement hormonal substitutif de la ménopause, des mutations du gène KRAS et le risque de cancer colorectal
Background: Postmenopausal hormone (PMH) therapy represents a controversial colorectal cancer (CRC) preventive intervention. Since colorectal carcinogenesis is a heterogeneous process, we evaluated associations between PMH therapy and incident CRC in relation to KRAS mutation status in a population-based cohort of older women (Iowa Women's Health Study [IWHS]). Methods: The IWHS enrolled 41,836 randomly selected women, ages 55-69 years, in 1986. PMH therapy and other exposure data were recorded at baseline. Tissue samples from prospectively identified CRC cases (n = 507) were analyzed for somatic KRAS mutations (exon 2, codons 12 and 13). Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: PMH therapy (ever vs. never) was inversely associated with KRAS mutation-negative (RR = 0.83; 95% CI = 0.66-1.06; p = 0.14) and KRAS mutation-positive (RR = 0.82; 95% CI = 0.58-1.16; p = 0.27) tumors, although the observed risk estimates were not statistically significant. When anatomic subsite was additionally considered, the strongest association was found for KRAS mutation-negative, distal colorectal tumors (RR = 0.64; 95% CI = 0.43-0.96; p = 0.03). Conclusions: To our knowledge, we provide the first report of KRAS-defined CRC risks associated with PMH therapy. These data suggest that PMH therapy may reduce CRC risk through mechanisms beyond KRAS mutation status, but might provide greater benefits for KRAS mutation-negative than mutation-positive tumors (at least in the distal colorectum). Impact: Findings from this prospective cohort study provide novel insights regarding the molecular biology of PMH therapy-related CRC risk reduction.