Colorectal cancer (CRC) has a high global impact as the second leading cause of cancer associated deaths. There are several preventive measures that can reduce your risk of developing colorectal cancer including physical activity and polyp removal performed during a colonoscopy. There is also increasing data to suggest that women who take hormone therapy to manage symptoms of menopause—hot flashes, night sweats, vaginal dryness, depression, insomnia, etc.—have reduced risk of developing colorectal cancer. Dr. Ulrike (Riki) Peters, a Professor and Associate Director of the Public Health Sciences Division at Fred Hutchinson Cancer Center, has been exploring this connection. “We asked the question if the genetic background of a women impacts the effect of hormone therapy on CRC risk.” shared Dr. Peters. In collaboration with Dr. Li Hsu, a Professor in Public Health Sciences Division, and several others, they discovered that women who have high genetic risk factors for colorectal cancer experience greater risk reducing effects of hormone therapy than women without these underlying genetic risk factors. Their findings were published recently in the British Journal of Cancer.
“Women are faced with a complex decision when reaching menopause: if they should take hormone therapy or not,” stated Dr. Peters. Women are often curious about how their genes will affect their risk of developing CRC and if hormone therapy impacts this risk prediction, continued Dr. Peters. To investigate how hormone therapy affects colorectal cancer risk for women with or without genetic risk factors, the researchers took significant efforts to compile an extensive dataset. Yi Lin, a member of the Peters Group and co-first author of this work commented that “this research project was only possible because we were able to build a large consortium of over 60 observational studies for CRC across Asia, Australia, Europe, and America, which allowed us to discover many genetic risk factors for CRC.” For our complete dataset, “we harmonized the clinical, lifestyle and environmental data across these studies to allow us to investigate interactions between lifestyle and environmental factors and genetic variants,” continued Lin. This large-scale effort included more than 28,000 post-menopausal women and about 10,000 used menopausal hormone therapy. A 30-year cumulative risk assessment was conducted by dividing the women into four quartiles based on increasing genetic risk for colorectal cancer from quartile 1 (Q1, those in lowest 25 % of genetic risk) to quartile 4 (Q4, those in the highest 25% of risk). The menopausal hormone therapy group had consistently lower overall predicted risk of colorectal cancer in each of these genetic based risk groups as compared to women not taking menopausal hormone therapy. Of note, the Q4 which is the highest genetic risk group had the largest risk reduction, supporting an increased benefit of hormone therapy with increasing genetic risk. These findings confirm that menopausal hormone therapy correlates with reduced risk of colorectal cancer with the most benefit attributed to those who have more genetic risk factors. “This is of interest to women as it provides those women who have a higher genetic predisposition to develop CRC an opportunity (beyond screening) to reduce their risk by taking hormones,” commented Flora Qu, a member of the Peters Group.
While menopausal hormone therapy might seem like the golden ticket for women to reduce their risk of colorectal cancer, this type of therapy can influence the outcome of several other diseases—breast cancer, osteoporosis, and cardiometabolic diseases. Dr. Peters explained, “It is of note that for some [diseases], like osteoporosis, hormone therapy reduces the risk and for others, like stroke hormone therapy increase the risk.” This makes the decision to start menopausal hormone therapy a challenging one. “As a next step we are conducting a study within the Women’s Health Initiative, which was key to discovering the various effects of hormone therapy,” continued Dr. Peters. “In this ongoing study we aim to more comprehensively investigate how the genetic background of a woman impacts the effect of hormone therapy on these various diseases, not just CRC.” Dr. Hsu pointed out a limitation of the study, noting that “most studies have been conducted decades ago and cannot test some of the newer hormone therapies now available, such as dermal or intervaginal devices. To address this question, new studies are needed.” Women reaching menopause must decide whether menopausal hormone therapy is a good option for them. This study and future work from the Peters and Hsu Groups will provide insight into this complicated topic and help women make this challenging decision.
The spotlighted research was funded by the National Institutes of Health, Ontario Research Fund, Canadian Institutes of Health Research, Canadian Cancer Society, Ontario Ministry of Research and Innovation, Daniel and Maryann Fong, Instituto de Salud Carlos III, FEDER funds, Catalan Government, Junta de Castilla y León, The Spanish Association Against Cancer, German Research Council, National Center for Tumor Diseases, German Federal Ministry of Education and Research, International Agency for Research on Cancer, Imperial College London, Baden Wurttemberg Ministry of Science, Research and Arts and the German Cancer Aid, and others.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Ross Prentice, Ulrike Peters and Li Hsu contributed to this work.
Tian Y, Lin Y, Qu C, Arndt V, Baurley JW, Berndt SI, Bien SA, Bishop DT, Brenner H, Buchanan DD, Budiarto A, Campbell PT, Carreras-Torres R, Casey G, Chan AT, Chen R, Chen X, Conti DV, Díez-Obrero V, Dimou N, Drew DA, Figueiredo JC, Gallinger S, Giles GG, Gruber SB, Gunter MJ, Harlid S, Harrison TA, Hidaka A, Hoffmeister M, Huyghe JR, Jenkins MA, Jordahl KM, Joshi AD, Keku TO, Kawaguchi E, Kim AE, Kundaje A, Larsson SC, Marchand LL, Lewinger JP, Li L, Moreno V, Morrison J, Murphy N, Nan H, Nassir R, Newcomb PA, Obón-Santacana M, Ogino S, Ose J, Pardamean B, Pellatt AJ, Peoples AR, Platz EA, Potter JD, Prentice RL, Rennert G, Ruiz-Narvaez EA, Sakoda LC, Schoen RE, Shcherbina A, Stern MC, Su YR, Thibodeau SN, Thomas DC, Tsilidis KK, van Duijnhoven FJB, Van Guelpen B, Visvanathan K, White E, Wolk A, Woods MO, Wu AH, Peters U, Gauderman WJ, Hsu L, Chang-Claude J. 2024. Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk. Br J Cancer. 130(10):1687-1696.
Science spotlight writer Annabel Olson is a postdoctoral research fellow in the Nabet lab at Fred Hutchinson Cancer Center. Her research focuses on studying the mechanisms that drive cancer development for both genetic and virus-associated cancers. A key tool in her research is the use of targeted protein degradation to dissect dysregulated signaling pathways in cancer and to double as a relevant pre-clinical therapeutic platform.