Postmenopausal Hormone Therapy and Colorectal Cancer Risk by Molecularly Defined Subtypes and Tumor Location

Julia D Labadie; Tabitha A Harrison; Barbara Banbury; Efrat L Amtay; Sonja Bernd; Hermann Brenner; Daniel D Buchanan; Peter T Campbell; Yin Cao; Andrew T Chan; Jenny Chang-Claude; Dallas English; Jane C Figueiredo; Steven J Gallinger; Graham G Giles; Marc J Gunter; Michael Hoffmeister; Li Hsu; Mark A Jenkins; Yi Lin; Roger L Milne; Victor Moreno; Neil Murphy; Shuji Ogino; Amanda I Phipps; Lori C Sakoda; Martha L Slattery; Melissa C Southey; Wei Sun; Stephen N Thibodeau; Bethany Van Guelpen; Syed H Zaidi; Ulrike Peters; Polly A Newcomb

doi:10.1093/jncics/pkaa042

Postmenopausal Hormone Therapy and Colorectal Cancer Risk by Molecularly Defined Subtypes and Tumor Location

JNCI Cancer Spectr. 2020 May 19;4(5):pkaa042. doi: 10.1093/jncics/pkaa042. eCollection 2020 Aug.

Authors

Julia D Labadie^{1

2}, Tabitha A Harrison¹, Barbara Banbury¹, Efrat L Amtay³, Sonja Bernd⁴, Hermann Brenner^{3

5}, Daniel D Buchanan⁶, Peter T Campbell⁷, Yin Cao^{8

9

10}, Andrew T Chan^{11

12}, Jenny Chang-Claude^{13

14}, Dallas English^{15

16}, Jane C Figueiredo^{17

18}, Steven J Gallinger¹⁹, Graham G Giles^{15

16

20}, Marc J Gunter²¹, Michael Hoffmeister³, Li Hsu^{1

22}, Mark A Jenkins¹⁶, Yi Lin¹, Roger L Milne^{15

16

20}, Victor Moreno²³, Neil Murphy²¹, Shuji Ogino²⁴, Amanda I Phipps^{1

2}, Lori C Sakoda^{1

25}, Martha L Slattery²⁶, Melissa C Southey^{15

20

27}, Wei Sun¹, Stephen N Thibodeau²⁸, Bethany Van Guelpen²⁹, Syed H Zaidi³⁰, Ulrike Peters^{1

2}, Polly A Newcomb^{1

2}

Affiliations

¹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
² Department of Epidemiology, University of Washington, Seattle, WA, USA.
³ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁶ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
⁷ Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
⁸ Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA.
⁹ Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St Louis, MO, USA.
¹⁰ Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
¹¹ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
¹² Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹³ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁴ University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
¹⁵ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
¹⁶ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁷ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai, Los Angeles, CA, USA.
¹⁸ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁹ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
²⁰ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
²¹ Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
²² Department of Biostatistics, University of Washington, Seattle, WA, USA.
²³ Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
²⁴ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁵ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
²⁶ Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
²⁷ Genetic Epidemiology Laboratory, Department of Clinical Pathology, University of Melbourne, Melbourne, Victoria, Australia.
²⁸ Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²⁹ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
³⁰ Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

Abstract

Background: Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location.

Methods: We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided.

Results: Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; P _het=.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; P _het=.01) tumors.

Conclusions: We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.

Abstract

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