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Date of release: 13 June, 2016

Hormone therapy and large bowel cancer revisited

Colorectal cancer is among the most common malignancies in the Western world. Many studies have investigated a potential association between postmenopausal hormone therapy (HT) and risk for colorectal cancer. The latest study on this topic has just appeared [1]. Data on HT use were retrieved from the Danish National Prescription Register, and those on cancer from the National Cancer Registry. The cohort was huge (n = 1,006,219 women 50-79 years old without previous cancer), which allowed the extraction of information concerning 8377 cases of colon cancer and 4742 cases of rectal cancer. Use of estrogen-only therapy and use of combined hormonal therapy were associated with decreased risks of colon cancer (adjusted incidence rate ratio 0.77 (95% CI 0.68-0.86) and 0.88 (95% CI 0.80-0.96)) and rectal cancer (0.83 (95% CI 0.72-0.96) and 0.89 (95% CI 0.80-1.00)) compared to never users. Transdermal estrogen-only therapy provided more protection than oral administration, while no significant influence was found in regard to regimen or progestin type. The benefit of HT was stronger for long-term hormone users, and hormone users were at lower risk of advanced stage of colorectal cancer.

Comment

Large series at the end of the previous millennium already pointed at a protective effect of postmenopausal hormone therapy on the risk of large bowel cancer. Here are a few examples: the Nurses' Health Study was based on self-reported data in 59,000 women [2]. During a period of 14 years, 470 women developed colorectal cancer, and 838 developed distal colorectal adenomas. Current use of postmenopausal hormones was associated with a decreased risk for colorectal cancer (RR 0.65; 95% CI 0.50-0.83). This association was attenuated in past users (RR 0.84; 95% CI 0.67-1.05) and disappeared 5 years after hormone use was discontinued. Longer duration of current use (≥ 5 years of use) did not confer greater protection. There was also a 26% reduction in risk for adenomas >1 cm. In another study in the United States among 40,000 postmenopausal women, 41-80 years of age, who initially volunteered for a nationwide breast-cancer screening program and were followed for an average of 7.7 years, ever-use of menopausal hormones was not associated with risk of total colorectal cancers (RR 0.99) [3]. However, recent hormone users demonstrated a small non-significant reduction in risk of colorectal cancer (RR 0.78; 95% CI 0.55-1.1). The reduced risk for recent users was stronger for users of 5 or more years' duration. No effect was observed for former hormone users, and risk generally did not vary by time since last use, type of regimen, or duration of use. Data from Europe pointed at a protective effect [4]: ever use of HT was inversely associated with cancer of the colon (OR 0.64; 95% CI 0.46-0.88) and of the rectum (OR 0.46; 95% CI 0.29-0.72) when compared to never users. Increasing duration of use of HT was related to decreasing risk for colon and rectal cancers.

While these were all observational studies, the WHI study provided data from a randomized, double-blind, placebo-controlled trial. In 2004, the results from the conjugated equine estrogen plus medroxyprogesterone acetate cohort were published, showing a beneficial outcome [5]. The study was terminated earlier than scheduled; nevertheless, during a mean 5.6-year follow-up period in a cohort which included 16,608 postmenopausal women 50-79 years of age, the hazard ratio (HR) was 0.56 (95% CI 0.38-0.81) when the HT arm was compared with the placebo arm. The downside of these results was that hormone users had more positive lymph nodes and their disease stage was more advanced (regional or metastatic disease). Furthermore, in 2012, data from a combined analysis of the initial study period plus a post-interventional period (mean 11.6 years of total follow-up) pointed at diagnosis of fewer colorectal cancers in the combined hormone therapy group compared with the placebo group (HR 0.72; 95% CI 0.56-0.94) [6]. Once again, cancers in the HT group more commonly had positive lymph nodes and were at a higher stage. Although not statistically significant, there was a higher number of colorectal cancer deaths in the HT group (37 vs. 27 deaths; HR 1.29; 95% CI 0.78-2.11). In a very similar way, the results of the conjugated equine estrogen-alone therapy in the WHI study among 10,739 postmenopausal women (aged 50-79 years) with prior hysterectomy were released in 2004, and the extended post-intervention follow-up data were published in 2015 [7, 8]. There were 119 cases of colorectal neoplasia during the active phase (mean 6.8 years), and the HR was 1.08 (95% CI 0.75-1.55) when estrogen users were compared to placebo [7]. In the cumulative follow-up of 13.2 years, colorectal cancer rates in the estrogen-alone and placebo groups were comparable (HR 1.13; 95% CI 0.83-1.58) [8].

On the whole, it seems most likely that HT has beneficial effects on the incidence of colorectal cancer in postmenopausal women. However, the impact on health may not be substantial as the absolute numbers point at the order of only a few saved cases per 10,000 women per year of hormone use. In addition, the issue of a potential impact of hormone use on survival from large bowel cancer remains to be further clarified [9].

Amos Pines


Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel



    References

  1. Mørch LS, Lidegaard Ø, Keiding N, Løkkegaard E, Kjær SK. The influence of hormone therapies on colon and rectal cancer. Eur J Epidemiol 2016 Jan 12. Epub ahead of print


    http://www.ncbi.nlm.nih.gov/pubmed/26758900

  2. Grodstein F, Martinez ME, Platz EA, et al. Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann Intern Med 1998;128:705-12


    http://www.ncbi.nlm.nih.gov/pubmed/9556463

  3. Troisi R, Schairer C, Chow WH, et al. A prospective study of menopausal hormones and risk of colorectal cancer (United States). Cancer Causes Control 1997;8:130-8


    http://www.ncbi.nlm.nih.gov/pubmed/9134236

  4. Fernandez E, La Vecchia C, Braga C, et al. Hormone replacement therapy and risk of colon and rectal cancer. Cancer Epidemiol Biomarkers Prev 1998;7:329-33


    http://www.ncbi.nlm.nih.gov/pubmed/9568789

  5. Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 2004;350:991-1004


    http://www.ncbi.nlm.nih.gov/pubmed/14999111

  6. Simon MS, Chlebowski RT, Wactawski-Wende J, et al. Estrogen plus progestin and colorectal cancer incidence and mortality. J Clin Oncol 2012;30:3983-90


    http://www.ncbi.nlm.nih.gov/pubmed/23008295

  7. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-12


    http://www.ncbi.nlm.nih.gov/pubmed/15082697

  8. Lavasani S, Chlebowski RT, Prentice RL, et al. Estrogen and colorectal cancer incidence and mortality. Cancer 2015;121:3261-71


    http://www.ncbi.nlm.nih.gov/pubmed/26036212

  9. Newcomb PA, Chia VM, Hampton JM, Doria-Rose VP, Trentham Dietz A. Hormone therapy in relation to survival from large bowel cancer. Cancer Causes Control 2009;20:409-16


    http://www.ncbi.nlm.nih.gov/pubmed/18998219