Postmenopausal hormone therapy and colorectal cancer risk by molecularly defined subtypes among older women.
BACKGROUND
Postmenopausal hormone (PMH) therapy may reduce colorectal cancer (CRC) risk, but existing data are inconclusive.


OBJECTIVE
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.
Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA. limburg.paul@mayo.edu
David
D
Limsui
Robert A
RA
Vierkant
Lori S
LS
Tillmans
Alice H
AH
Wang
Daniel J
DJ
Weisenberger
Peter W
PW
Laird
Charles F
CF
Lynch
Kristin E
KE
Anderson
Amy J
AJ
French
Robert W
RW
Haile
Lisa J
LJ
Harnack
John D
JD
Potter
Susan L
SL
Slager
Thomas C
TC
Smyrk
Stephen N
SN
Thibodeau
James R
JR
Cerhan
Paul J
PJ
Limburg
D000368:Aged; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000145:classification / Q000453:epidemiology* / Q000235:genetics; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D015994:Incidence; D007484:Iowa; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D017698:Postmenopause; D016016:Proportional Hazards Models; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012042:Registries; D018570:Risk Assessment; D011795:Surveys and Questionnaires
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf