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Journal of Clinical Oncology, Vol 24, No 36 (December 20), 2006: pp. 5680-5686 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.0580 Hormone Replacement Therapy and Survival After Colorectal Cancer Diagnosis
From the Dana-Farber Cancer Institute; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; and Massachusetts General Hospital, Boston, MA Address reprint requests to Jennifer A. Chan, MD, MPH, Dana-Farber Cancer Institute, Dana 1220, 44 Binney St, Boston, MA 02115; e-mail: jang{at}partners.org
PURPOSE: Postmenopausal estrogen use has been shown to decrease the incidence of colorectal cancer, but there is limited information regarding the effect of estrogen use on survival after diagnosis of colorectal cancer. PARTICIPANTS AND METHODS: We examined the influence of postmenopausal estrogen use on mortality among 834 women participating in the Nurses' Health Study who were diagnosed with colorectal cancer between 1976 and 2000 and observed until death or June 2004, whichever came first. Colorectal cancer–specific mortality and overall mortality according to categories of hormone use were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) adjusted for other risk factors for cancer survival. RESULTS: Postmenopausal estrogen use before diagnosis of colorectal cancer was associated with significant reduction in mortality. Compared with women with no prior estrogen use, those reporting current use before diagnosis had an adjusted HR of 0.64 (95% CI, 0.47 to 0.88) for colorectal cancer–specific mortality and 0.74 (95% CI, 0.56 to 0.97) for overall mortality. This inverse association between hormone use and mortality was most evident among women whose duration of use was less than 5 years. Longer durations and past use were not associated with significant survival benefit. Assessment of estrogen use after diagnosis demonstrated similar findings. CONCLUSION: Current postmenopausal estrogen use before diagnosis of colorectal cancer was associated with improved colorectal cancer–specific and overall mortality. This benefit was principally limited to women who initiated estrogens within 5 years of diagnosis. Additional efforts to understand mechanisms through which estrogens influence colorectal carcinogenesis and cancer progression seem warranted.
Numerous studies have demonstrated that postmenopausal estrogen use confers significant reduction in risk of colorectal cancer.1-11 A meta-analysis of 18 epidemiologic studies found a 20% decrease in risk of colon cancer associated with any use of postmenopausal hormones; a similar association was observed with rectal cancer.10 Current use of postmenopausal estrogens was associated with a stronger risk reduction (relative risk = 0.66; 95% CI, 0.59 to 0.74), suggesting that recent hormone use may be a more relevant exposure for colorectal cancer etiology. Further substantiating this association, a large placebo-controlled, randomized trial (the Women's Health Initiative) demonstrated a 39% reduction in colorectal cancer incidence among women assigned to estrogen plus progestin therapy.11 In contrast, the influence of postmenopausal estrogen use on survival of patients with established colorectal cancer remains uncertain. In two studies of women with colorectal cancer, postmenopausal hormone use was associated with a 30% to 40% improvement in overall survival.12,13 However, these studies were limited by assessment of hormone use after diagnosis and lack of detailed data regarding hormone use and other potential confounding factors. Therefore, we prospectively examined the influence of postmenopausal hormone therapy on survival of women diagnosed with colorectal cancer while participating in a large, prospective cohort study (Nurses' Health Study [NHS]). Because detailed and updated hormone use data were assessed before and after diagnosis of colorectal cancer, we were able to analyze the influence of both pre- and postdiagnosis estrogen use while adjusting for other predictors of cancer survival.
Study Population In 1976, the NHS cohort was established when 121,700 female registered nurses from across the United States, aged 30 to 55 years, answered a mailed questionnaire on risk factors for cancer and cardiovascular disease. Every 2 years, participants have been sent follow-up questionnaires to update information on potential risk factors and to identify women newly diagnosed with cancer and other diseases. This study was approved by the Human Subjects Committee at Brigham and Women's Hospital in Boston, Massachusetts. Completion of the self-administered questionnaires was considered to imply informed consent.
Measurement of Colon Cancer
Measurement of Mortality
Identification of Participants
Exposure Assessment
Covariates
Statistical Analyses
Among 834 eligible participants with colorectal cancer, there were 376 deaths, of which 298 were classified as colorectal cancer–specific deaths. Baseline characteristics of participants according to categories of hormone use immediately before diagnosis of colorectal cancer are listed in Table 1. In general, current hormone users were less likely to have stage IV cancer but more likely to have stage III disease; moreover, women using hormones at diagnosis were more likely to have been diagnosed with cancer after 1990 compared with women who never used hormones. Prediagnosis hormone use was assessed at a median of 12 months before diagnosis (10th and 90th percentiles, 2 and 22 months, respectively). Postdiagnosis assessments were performed at a median of 11 months after diagnosis (10th and 90th percentiles, 3 and 22 months, respectively).
Hormone Use Before Diagnosis We assessed the influence of postmenopausal estrogen use immediately before diagnosis of colorectal cancer on patient survival (Table 2). Current postmenopausal estrogen use was associated with significant reductions in risk of colorectal cancer–specific and overall mortality. These relationships remained largely unchanged after adjusting for other predictors of cancer recurrence. Compared with women who never used hormones, current users experienced a multivariate HR for cancer-specific mortality of 0.64 (95% CI, 0.47 to 0.88). Similarly, the multivariate HR for overall mortality was 0.74 (95% CI, 0.56 to 0.97).
The association between hormone use and reduced mortality did not increase with longer duration of hormone use (Table 2). Compared with women who had never received hormones, the multivariate HR for colorectal cancer–specific mortality among current hormone users who had used hormones for less than 5 years was 0.39 (95% CI, 0.23 to 0.67). In contrast, among those who took hormones for 5 or more years, the multivariate HR for colorectal cancer–specific mortality was 0.83 (95% CI, 0.58 to 1.18); for those who had used hormones for 10 or more years, the multivariate HR was 0.89 (95% CI, 0.58 to 1.36). Similarly, a significant reduction in all-cause mortality was limited to current users who had received hormones for less than 5 years. No significant inverse relation was observed for long-term or past users. The benefit associated with postmenopausal hormone use did not differ according to estrogen dose (P for trend = .76); however, because the vast majority of users reported a dose of 0.625 mg/d, statistical power to examine estrogen dose was limited.
We explored whether the influence of estrogen use on survival was modified by BMI. The inverse relationship between current hormone use and mortality did not differ significantly according to categories of BMI (P value for interaction = .11 and .17 for cancer-specific and overall mortality, respectively). Among normal and underweight women (BMI < 25 kg/m2), the multivariate HRs for cancer-specific and overall mortality among current hormone users compared with never users were 0.66 (95% CI, 0.42 to 1.03) and 0.78 (95% CI, 0.53 to 1.15), respectively. Similarly, among overweight and obese women (BMI We assessed 5- and 10-year survival according to categories of postmenopausal estrogen use measured immediately before cancer diagnosis. The 5-year colorectal cancer–specific survival rate was 78% for current hormone users, 70% for past users, and 64% for never users (Fig 1); the corresponding 10-year colorectal cancer–specific survival rates were 71%, 62%, and 60%, respectively.
We considered the possibility that, among patients with advanced disease, hormone use may be associated with lesser burden of disease. Therefore, we repeated our analyses after excluding women with stage IV (metastatic) disease (Table 3). Nonetheless, we continued to observe significant reductions in risk of colorectal cancer–specific and overall mortality among current hormone users. Compared with women who had never taken hormones, the multivariate HRs for women currently using hormones for less than 5 years at diagnosis were 0.40 (95% CI, 0.20 to 0.82) and 0.49 (95% CI, 0.27 to 0.89) for colorectal cancer–specific and overall mortality, respectively. Consistent with the analysis of all patients, a significant inverse association was not observed among women with longer duration of current hormone use or past hormone use. We found comparable results in an analysis limited only to women with stage IV disease.
Hormone Use After Diagnosis We also assessed survival according to postmenopausal hormone use immediately after diagnosis of colorectal cancer (Table 4). Use of hormones after diagnosis was highly correlated with use before diagnosis; 84% of women who reported current use of hormones after diagnosis were current hormone users before diagnosis. Similar to what was observed before diagnosis, current hormone use after diagnosis was associated with a multivariate HR of 0.56 (95% CI, 0.34 to 0.92) for colorectal cancer–specific mortality and 0.69 (95% CI, 0.47 to 1.03) for all-cause mortality. Moreover, a significant reduction in all-cause mortality was principally limited to current users who had received hormones for less than 5 years, whereas long-term past use conferred no benefit.
Because the decision to avoid exogenous estrogen use could reflect occult cancer recurrence or impending death, we excluded patients who died within 6 months of providing information about postdiagnosis hormone use. Nonetheless, to further address this issue, we repeated our analyses after excluding patients who died within 12 months of reporting hormone use. Although statistical power was diminished by this more stringent exclusion, women reporting current hormone use after colorectal cancer diagnosis had a multivariate HR of 0.59 (95% CI, 0.33 to 1.03) for colorectal cancer–specific mortality and 0.73 (95% CI, 0.48 to 1.12) for all-cause mortality compared with women with no prior hormone exposure.
We found that current use of postmenopausal estrogen before diagnosis of colorectal cancer was associated with a decreased risk of colorectal cancer–specific death and death from any cause. This benefit was principally limited to women who initiated estrogens within 5 years of diagnosis of colorectal cancer. Increased duration of hormone use (> 5 years) and past use were not associated with improvements in survival. Our findings are consistent with earlier studies evaluating the relationship of postmenopausal hormone use and survival after diagnosis with colorectal cancer. In an analysis using information about hormone use assessed after diagnosis, Slattery et al12 reported a 40% reduction in risk of death as a result of colon cancer and a 30% reduction in all-cause morality among women who reported recent hormone use. Similarly, Mandelson et al13 found that hormone use among women with colon cancer, as ascertained from pharmacy records, was associated with a 41% reduction in cancer-related death (HR = 0.59; 95% CI, 0.35 to 0.97). In contrast to these earlier studies, the current study provides data on hormone use collected prospective to diagnosis of colorectal cancer, detailed information on disease stage, and long-term follow-up. Moreover, our results extend these findings by providing information regarding the impact of timing and duration of hormone use on survival. There are several mechanisms through which hormone exposure may protect against development of colon cancer as well as improve survival after diagnosis of colon cancer. Exogenous estrogens could lead to slower disease progression. Several studies have demonstrated that estrogen inhibits cell growth in human colon cancer cell lines and that loss of estrogen results in increased proliferation of normal colonic cells.19-21 In addition, exogenous estrogens have been associated with prevention of methylation-associated changes that inactivate the estrogen receptor and can result in increased cell growth.22 Alternatively, estrogens may inhibit cancer progression through other mechanisms. Our finding that longer duration of hormone use was not associated with improved survival might seem inconsistent with our overall results. However, it is possible that cancers that develop in the setting of long-term exogenous estrogen exposure may be less responsive to the growth-inhibiting effects of estrogen. Specifically, the benefit for estrogen on established colorectal cancer may be confined to women with cancers who have had minimal prior exposure to exogenous estrogen. Several limitations of our study deserve comment. Beyond cause of mortality, data on cancer recurrences were not available. Nonetheless, because the median survival time for recurrent (metastatic) colorectal cancer was approximately 10 to 12 months during much of the time period under study, colorectal cancer–specific mortality should be a reasonable surrogate for cancer-specific outcomes. Although we do not validate self-reported hormone use in our cohort, we believe the reports to be accurate because study participants were registered nurses with a demonstrated interest in medical research. Validation of several other self-reported exposures in these nurses, such as diet,23 alcohol intake,24 BMI,25 and physical activity,26 have substantiated this belief. Moreover, the prospective design of our study eliminates recall bias, which can be a problem in retrospective study designs. The presence of a healthy user bias has been discussed in observational studies of postmenopausal hormones and mortality.27 Specifically, it is possible that women with advanced colorectal cancer may have developed symptoms leading to discontinuation of hormone use, thus classifying women with better prognosis as current hormone users and those with worse prognosis as past users. To address this issue, we evaluated hormone use according to the last biennial questionnaire completed before diagnosis of colorectal cancer. Moreover, our findings remained unchanged after adjusting for other potential risk factors for colorectal cancer mortality or excluding women with metastatic disease. Furthermore, in our analyses of the impact of postdiagnosis hormone use, we excluded participants who died within 6 months of providing information regarding use of hormone therapy to minimize bias related to occult recurrence or impending death. We continued to observe an inverse association between current hormone use and death when we extended this restriction to 12 months. We also considered the possibility that women receiving hormones might have a different prognosis related to more frequent use of screening procedures. Compared with women who had undergone screening endoscopy, women who had not undergone screening were more likely to have stage III or IV disease (49% v 36%, respectively; P = .001, Fisher's exact test). Although adjusting for disease stage would largely correct for such biases, we further addressed this concern by repeating our analyses after adjusting for utilization of screening endoscopy any time before diagnosis. Adjustment for screening practices did not materially alter our results; compared with women who never used hormones, current users experienced a multivariate HR for cancer-specific mortality of 0.64 (95% CI, 0.47 to 0.88); the multivariate HR for all-cause mortality was 0.74 (95% CI, 0.56 to 0.98). In this cohort, data on treatment were limited. The majority of women had stage I or II disease, for which surgery alone generally would have been the standard of care. In stage-stratified analyses, there were no significant differences in receipt of chemotherapy according to hormone use. Among women with stages III and IV disease who provided therapy-related information, 90% of women currently using hormones before diagnosis received chemotherapy compared with 90% of women who never used hormones and 94% of women who used hormones in the past (P = .99, Fisher's exact test). Additionally, although there have been changes in patterns of hormone use and treatments of colorectal cancer during the timeframe under study that could influence outcome, we have adjusted for year of diagnosis in our multivariate models for survival. Furthermore, although there are differences in likelihood of chemotherapy receipt based on factors such as socioeconomic status, the fairly homogeneous socioeconomic and educational makeup of this cohort likely minimizes such disparities in the delivery of standard therapy.28 In summary, our data suggest that initiation of postmenopausal estrogen therapy 5 or fewer years before the diagnosis of colorectal cancer is associated with significant improvement in colorectal cancer–specific survival and overall survival. Recent concerns regarding the potential increased risk of breast cancer and cardiovascular disease as a result of hormone-replacement therapy has substantially diminished routine use of estrogens. However, it is possible that agents possessing similar estrogenic activity without such adverse effects may offer benefits for patients with colorectal cancer. Additional efforts to understand the mechanisms through which estrogens influence colorectal carcinogenesis and cancer progression appear warranted.
The authors indicated no potential conflicts of interest.
Supported by Grant No. T32 CA 09001 from the National Institutes of Health (J.A.C.). The Nurses' Health Study is supported in part by Grant No. P01CA087969 from the National Cancer Institute. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
25 kg/m2), the multivariate HRs for cancer-specific and overall mortality among current hormone users compared with never users were 0.64 (95% CI, 0.40 to 1.03) and 0.70 (95% CI, 0.46 to 1.05). 
