Background
Colorectal cancer is the third most common cause of cancer mortality in women, with 0.8 million new cases in 2018 worldwide [
1]. The advances in treatment of colorectal cancer has translated to a marked improvement in survivorship in the past decades [
1]. From 1995 to 2014, the 5-year survival was increased by 5–10% in various countries [
2]. Given the aging population and advances in treatment in the past decades, the 5-year colorectal cancer prevalence in women were estimated to be over 2 million in 2018 [
3]. Despite these encouraging figures, the cumulative impact of cancer and ongoing chronic physical and emotional symptoms reduce quality of life and overall survival [
4].
Identification of factors associated with better prognosis among colorectal cancer survivors has important implications to inform provision of survivorship care. Extensive evidence from observational studies and clinical trials suggests that hormone replacement therapy (HRT) might have protective effect against colorectal cancer incidence. A meta-analysis of four randomized control trials and 16 observational studies showed a 26% reduction in colorectal cancer risk associated with any use of combined estrogen and progestin [
5]. Similar association was observed for estrogen-only HRT despite considerable between-study heterogeneity [
5]. However, previous evidence only focused on the association between HRT and colorectal cancer risk [
5]. The role of HRT use on risk of mortality in patients diagnosed with colorectal cancer remains uncertain. A comprehensive evaluation of the impact of hormone therapy use among cancer survivors is urgently needed to inform physicians and patients for treatment decision making.
In this systematic review and meta-analysis, we aimed to summarize the available evidence and to quantify the association of HRT with colorectal-specific and all-cause mortality in women with diagnosis of colorectal cancer.
Discussion
In this study, we performed a systematic review and meta-analysis, synthesising non-overlapping data from 10,013 colorectal cancer survivors, to quantify the association between HRT use and risk of mortality. The study findings show that the current use of HRT was associated with a significant reduction in the risk of colorectal cancer-specific mortality and all-cause mortality in women with colorectal cancer. In contrast, the former use of HRT was not associated with lower all-cause and colorectal cancer mortality in colorectal cancer survivors. Findings for the prediction interval were consistent with the main estimates. In sensitivity analysis, these results were not significantly affected in influence analysis. No differences were noted between two groups in the risk estimates using the fixed-effect meta-analysis.
Extensive evidence from clinical trials and observational studies have shown the use of HRT to be associated with a reduction in colorectal cancer risk in women [
5]. In addition to the well-documented chemoprevention effects, our results also suggested a role of HRT on disease-specific and all-cause mortality among colorectal cancer survivors. There are potential mechanisms underlying the association between HRT and colorectal cancer and all-cause mortality in colorectal cancer survivors. As colorectal cancer may be a hormone-dependent cancer, tumor progression is inversely associated with expression of Estrogen Receptor Beta (ERß) [
18,
19]. Konstantinopoulos and colleagues reported a significantly lower ERß expression in colon cancer cells compared with normal colon epithelium [
20]. The reduction of ERß expression in colorectal cancer might be associated with loss of differentiation [
20] and advanced cancer stages [
21]. Furthermore, potential of colorectal cancer progression was reportedly repressed by ERß expression [
19,
22]. Estrogen has been demonstrated to increase ERß expression [
19]. The downstream genomic protective effects of estrogen result in gene transcription related to angiogenesis and cellular adhesion. In addition, ERß has been reported to induce apoptosis via different mechanisms, including increased p53 signalling in LoVo colon cancer cells and increased DNA fragmentation in COLO205 colon cancer cells [
19]. In HT29 and SW480 colon cancer cells, ERß reduces cell proliferation via modulation of G1-phase cell cycle genes [
23]. Non-genomic effects of estrogen interaction with ERß include activation of various intracellular signaling pathways [
24]. Estrogenic regulation of c-Myc and cyclin D1 expression contributes to the inhibition of cell cycle progression [
24]. Furthermore, selective activation of ERß has an anti-carcinogenic effect on tumor microenvironment via the downregulation of inflammatory signaling (interleukin-6) [
19,
22].
To date, evidence is limited to determine whether the survival benefit of HRT among colorectal cancer survivors varies by dosage, duration, or timing of initiation. In our meta-analysis, among women diagnosed with colorectal cancer, the current HRT users had a reduced mortality risk compared with women with no prior hormone exposure, whereas risk was not changed for former users, suggesting that the association between HRT use and survivorship may be complicated and depend on the timing of hormone use. While evidence suggests that the current use of HRT has a survival benefit for colorectal cancer survivors, further rigorous assessment is needed to determine whether its possible adverse events such as venous thromboembolism outweighs the benefits. Because colorectal cancer is the third most common cancer in women [
1], affecting 1 in 41 women over their lifetime period [
25], our findings suggested that the potential favourable effects of HRT on mortality among colorectal cancer survivors justify further investigations.
Strength
To our knowledge, this is the first meta-analysis to assess the association between HRT and the risk of colorectal cancer-specific and all-cause mortality in colorectal cancer survivors. Prior reviews focused on the association between risk of colorectal cancer incidence and hormone therapy; however, our analysis provided a clinically relevant insight to the impact of HRT use on survival of patients with colorectal cancer. Another important strength of this study is that we provide predictive interval to express between-study heterogeneity in a random-effects meta-analysis. We did not observe significant between-study variance, which was reflected by the narrow predictive interval (0.58–0.86) and (0.63–0.87) for colorectal cancer-specific and all-cause mortality among current HRT users, respectively. Accordingly, it is likely that a future study will show a reduced mortality risk in colorectal cancer survivors with hormone replacement therapy compared with non-hormone users.
Limitation
There are several limitations that merit further discussion. First, owing to the study-level nature of the data and small numbers of studies, subgroup analyses and the assessment of publication bias were limited. Second, although we extensively searched for the best available evidence, studies identified in this analysis were from the United States and Sweden, which has limited the generalizability of the findings. However, we have provided prediction interval to provide the potential ranges of future studies. Third, meta-analyses of observational studies are susceptible to information bias. However, four of the five studies included were prospective design, which could minimize information bias. Also, in our meta-regression, no significant difference was observed between questionnaire assessment group or objective document group. Fourth, the mean follow-up period of included studies were relatively short, ranging from 4.0 to 7.7 years, which may be inadequate to reflect optimal long-term outcomes. Lastly, the ability to stratify the analyses by dose, duration, and types of hormone used was limited by the paucity of data, therefore, the pooled estimates represent a combined effect of estrogen and estrogen plus progesterone. Future research is needed to understand how these factors might influence survival of perimenopausal and postmenopausal women with a history of colorectal cancer.
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