Estrogen Plus Progestin and Colorectal Cancer Incidence and Mortality

and Alicia Young and Ross L. Prentice, Fred Hutchinson Cancer Research Center, Seattle, WA.
Journal of Clinical Oncology (Impact Factor: 18.43). 09/2012; 30(32). DOI: 10.1200/JCO.2012.42.7732
Source: PubMed


PURPOSEDuring the intervention phase in the Women's Health Initiative (WHI) clinical trial, use of estrogen plus progestin reduced the colorectal cancer diagnosis rate, but the cancers were found at a substantially higher stage. To assess the clinical relevance of the findings, analyses of the influence of combined hormone therapy on colorectal cancer incidence and colorectal cancer mortality were conducted after extended follow-up. PATIENTS AND METHODS
The WHI study was a randomized, double-blind, placebo-controlled clinical trial involving 16,608 postmenopausal women with an intact uterus who were randomly assigned to daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate (n = 8,506) or matching placebo (n = 8,102). Colorectal cancer diagnosis rates and colorectal cancer mortality were assessed.ResultsAfter a mean of 5.6 years (standard deviation [SD], 1.03 years) of intervention and 11.6 years (SD, 3.1 years) of total follow-up, fewer colorectal cancers were diagnosed in the combined hormone therapy group compared with the placebo group (diagnoses/year, 0.12% v 0.16%; hazard ratio [HR], 0.72; 95% CI, 0.56 to 0.94; P = .014). Bowel screening examinations were comparable between groups throughout. Cancers in the combined hormone therapy group more commonly had positive lymph nodes (50.5% v 28.6%; P < .001) and were at higher stage (regional or distant, 68.8% v 51.4%; P = .003). Although not statistically significant, there was a higher number of colorectal cancer deaths in the combined hormone therapy group (37 v 27 deaths; 0.04% v 0.03%; HR, 1.29; 95% CI, 0.78 to 2.11; P = .320). CONCLUSION
The findings, suggestive of diagnostic delay, do not support a clinically meaningful benefit for combined hormone therapy on colorectal cancer.

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    • "It should be pointed out that, due to the limited number of cases available in the subgroup analyses, the associations were rather modest. In the present study, we could not demonstrate the expected risk reduction of HRT use and CRC use, which is in contrast with findings from several previous studies [3,36-39], as well as with three large meta-analyses, demonstrating a significantly lower incidence of CRC with use of combined hormone therapy [7,40,41]. As regards associations with TNM stage in the entire cohort, we found a significantly reduced risk of T-stage 1 and 2 tumours, but not of any other particular subgroups of CRC. "
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    ABSTRACT: Background: Postmenopausal hormone therapy (HRT) and oral contraceptive (OC) use have in several studies been reported to be associated with a decreased colorectal cancer (CRC) risk. However, data on the association between HRT and OC and risk of different clinicopathological and molecular subsets of CRC are lacking. The aim of this molecular pathological epidemiology study was therefore to evaluate the associations between HRT and OC use and risk of specific CRC subgroups, overall and by tumour site. Method: In the population-based prospective cohort study Mamö Diet and Cancer, including 17035 women, 304 cases of CRC were diagnosed up until 31 December 2008. Immunohistochemical expression of beta-catenin, cyclin D1, p53 and MSI-screening status had previously been assessed in tissue microarrays with tumours from 280 cases. HRT was assessed as current use of combined HRT (CHRT) or unopposed oestrogen (ERT), and analysed among 12583 peri-and postmenopausal women. OC use was assessed as ever vs never use among all women in the cohort. A multivariate Cox regression model was applied to determine hazard ratios for risk of CRC, overall and according to molecular subgroups, in relation to HRT and OC use. Results: There was no significantly reduced risk of CRC by CHRT or ERT use, however a reduced risk of T-stage 1-2 tumours was seen among CHRT users (HR: 0.24; 95% CI: 0.09-0.77).Analysis stratified by tumour location revealed a reduced overall risk of rectal, but not colon, cancer among CHRT and ERT users, including T stage 1-2, lymph node negative, distant metastasis-free, cyclin D1 - and p53 negative tumours.In unadjusted analysis, OC use was significantly associated with a reduced overall risk of CRC (HR: 0.56; 95% CI: 0.44-0.71), but this significance was not retained in adjusted analysis (HR: 1.05: 95% CI: 0.80-1.37). A similar risk reduction was seen for the majority of clinicopathological and molecular subgroups. Conclusion: Our findings provide information on the relationship between use of HRT and OC and risk of clinicopathological and molecular subsets of CRC.
    BMC Cancer 05/2014; 14(1):371. DOI:10.1186/1471-2407-14-371 · 3.36 Impact Factor
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    ABSTRACT: Postmenopausal hormone therapy (PMHT) is used for the relief of menopausal symptoms, but the dosage has varied greatly throughout its existence. By the end of the 1990s, PMHT was mainly used to prevent chronic diseases such as osteoporosis, coronary heart disease and dementia, and large prevention trials were undertaken in this context. Following the initial negative reports of these trials, use of PMHT dramatically decreased. These reports noted surprisingly increased risks, notably of coronary heart disease, stroke and breast cancer, in people who used PMHT. Nowadays, considering the currently available data, it seems that an important distinction should be made between the treatment of climacteric symptoms in young, generally healthy, postmenopausal women and the prevention of chronic diseases in elderly women. PMHT seems to be beneficial and safe for postmenopausal symptomatic women aged <60 years. Treatments with a high safety profile should be the preferred option, including low-dose PMHT, oestrogen-only therapy in women who have had a hysterectomy, and vaginal oestrogen therapy for women with atrophic vaginitis. Nonandrogenic progestin might have a reduced thrombotic and breast cancer risk, and transdermal oestrogen could have a reduced thrombotic risk. Nevertheless, PMHT should not be used for the prevention of chronic diseases in the elderly (>70 years old) owing to the increased risk of stroke and breast cancer in these patients.
    Nature Reviews Endocrinology 02/2013; 9(4). DOI:10.1038/nrendo.2013.17 · 13.28 Impact Factor
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    ABSTRACT: An estimated 140,000 new cases of colorectal cancer (CRC) were diagnosed in the USA in 2013. This review focuses on primary, secondary, and tertiary efforts to improve outcomes for patients at risk of CRC. Primary prevention to prevent the occurrence of CRC should focus on the reduction of modifiable CRC risk factors, including education regarding the deleterious effects of Western diets consisting of red and processed meats and the dangers of a sedentary lifestyle and obesity. Foods containing folates, vitamin D, and calcium may be protective against CRC and their consumption should likely be encouraged. Secondary preventive screening efforts can have a profound effect on reducing mortality by identifying neoplasia when precancerous lesions such as adenomas may be removed or when early-stage CRCs exist. Efforts must be made to increase the uptake of CRC screening on a worldwide level. The most resounding data for pharmacologic success in the prophylaxis of colorectal neoplasia belong to the class of aspirin and nonsteroidal anti-inflammatory drugs. Future therapies improving the efficiency of CRC screening modalities and genomic medical breakthroughs to personalize prophylactic treatments will change the way CRC prevention is viewed.
    Current Colorectal Cancer Reports 03/2013; 10(1). DOI:10.1007/s11888-013-0201-6
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