Science Spotlight

The association between postmenopausal hormone therapy and colorectal cancer by molecular subtype and tumor location

From the Labadie Group and Newcomb Group

Colorectal cancer (CRC) can emerge from different channels defined by genetic and epigenetic events; it is a heterogenous disease. Currently, four tumor markers are generally used to indicate heterogeneity. The tumor markers are as follows: microsatellite instability (MSI), CpG island methylator phenotype (CIMP), somatic mutation in BRAF, somatic mutation in KRAS. There are three specific molecular pathways of colorectal carcinogenesis associated with these markers: adenoma-carcinoma, alternate, and, serrated.  Normally, these distinct pathways are identified via microscopic views of precancerous lesions and established in the early stages of disease pathogenesis. These tumors are specific in appearance, in predispositions for locations within the colon, have different biological behaviors, and may differ by epidemiological factors.

Previous literature reports that postmenopausal hormone therapy is associated with a reduced risk of CRC; recent analyses indicate a 20%-40% reduction in CRC risk. Only a few studies have assessed hormone therapy and its relationship with CRC risk by molecularly defined CRC subtypes.  It has been reported that the association of hormone therapy and CRC risk in regard to tumor location is stronger in distal colon tumors compared to proximal colon tumors.  The Labadie Group and Newcomb Group from the Division of Public Health Sciences are the first to evaluate tumor markers and location in association to hormone therapy use to further understand subtype- specific CRC risk.  In this study, four tumor markers were evaluated individually and with 3 pathways of colorectal carcinogenesis, which included tumor location.  This study was published in the JNCI Cancer Spectrum.

Data from 8 observational studies, the Colon Cancer Family Registry and the Genetics of Epidemiology of Colorectal Cancer Consortium, were pooled and included in the study. The inclusion criteria consisted of postmenopausal women with incident invasive CRC and data on tumor markers. Controls were available as well. Hormone therapy use was self-reported at baseline. Hormone therapy use included estrogen only and estrogen plus progestin.  DNA extracted from formalin-fixed, paraffin-embedded tumor tissue specimens were used for tumor marker testing; protocols varied for each individual marker. Tumor location data was obtained from pathology reports and registry.  A total of 3898 CRC cases and 4322 controls were included in the analysis.

Multinomial logistic regression was used to asses hormone therapy use and colorectal cancer; tumor marker status vs control was the outcome.  The Wald Chi Square test was used to evaluate heterogeneity in odds ratios. 

Graphical Representation of Association between postmenopausal hormone therapy (HT) use and colorectal cancer (CRC), overall and formulation specific.
Association between postmenopausal hormone therapy (HT) use and colorectal cancer (CRC), overall and formulation specific. Image from Dr. Labadie

Within the demographic characteristics, cases (32.4%) were less likely to be hormone therapy users than controls (42.8%). Also, cases were less likely to use estrogen-only (22.2% vs 29.7%) and estrogen plus progestin formulations (14.3% vs 17.8%) than controls.   Hormone therapy was associated with a reduced risk of colorectal cancer (OR=0.62, 95% CI=0.56-0.69).  Both estrogen only (OR=0.71, 95% CI= 0.62-0.83) and estrogen plus progestin formulations (OR=0.76, 95% CI=0.64-0.91) were significantly associated with decreased risk of CRC.   Hormone therapy and risk of CRC by tumor subtype was associated with a decreased risk of CRC as well. Hormone therapy use in the adenoma carcinoma (OR=0.63, 95% CI=0.55-0.73) and alternate pathways were significantly associated with a decreased risk of CRC (OR=0.61, 95% CI= 0.51-0.72).  Tumors from the serrated pathway were attenuated and not statistically significant.   The first author, Dr. Labadie, summarized the results for tumor location and pathway, “we saw the most benefit of hormone therapy use among tumors of the distal colon and rectum (vs. proximal colon) as well as tumors arising via the adenoma-carcinoma pathway (the most common pathway to develop colorectal cancer) and the ‘alternate’ pathway.”

Overall, the association of hormone therapy and CRC does not differ by the individual tumor markers, MSI, BRAF, and KRAS. With or without the presence of BRAF and KRAS in the models, strong inverse associations were observed for hormone therapy use and CRC risk. This study conducted by the Labadie Group and Newcomb Group was the largest study to evaluate hormone therapy use and CRC among individual tumor makers and location.  Dr. Labadie elaborates on the study’s findings. “If these findings can be replicated, they raise questions about the potential mechanisms underlying colorectal cancer subtypes. Further investigation into this finding can help researchers develop more targeted colorectal cancer treatments or preventive measures.”

This research was supported by the National Cancer Institute, National Institutes of Health, and US Department of Health and Human Services.

Fred Hutch/UW Cancer Consortium members Amanda I Phipps, Wei Sun, Ulrike Peters, and Polly A Newcomb contributed to this work.

Labadie JD, Harrison TA, Banbury B, Amtay EL, Bernd S, Brenner H, Buchanan DD, Campbell PT, Cao Y, Chan AT, Chang-Claude J. Post-menopausal hormone therapy and colorectal cancer risk by molecularly-defined subtypes and tumor location. JNCI Cancer Spectrum. 2020 May 19. https://doi.org/10.1093/jncics/pkaa042

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