Dig Dis Sci DOI 10.1007/s10620-014-3452-4

REVIEW

Colorectal Cancer Screening and Prevention in Women Lyssa Chacko • Carole Macaron • Carol A. Burke

Received: 15 August 2014 / Accepted: 16 November 2014 Ó Springer Science+Business Media New York 2015

Abstract Colorectal cancer (CRC) is one of the leading cancers and cause of cancer deaths in American women and men. Females and males share a similar lifetime cumulative risk of CRC however, substantial differences in risk factors, tumor biology, and effectiveness of cancer prevention services have been observed between them. This review distills the evidence documenting the unique variation observed between the genders relating to CRC risk factors, screening and prevention. Consistent evidence throughout the world demonstrates that women reach equivalent levels of adenomas and CRC as men but it occurs nearly a decade later in life than in their male counterparts. Women have a higher proportion of tumors which are hypermethylated, have microsatellite instability and located in the proximal colon suggesting the serrated pathway may be of greater consequence in them than in men. Other CRC risk factors such as smoking, diet and obesity have been shown to have disparate effects on women which may related to interactions between estrogen exposure, body fat distribution, and the biologic underpinnings of their tumors. There is data showing the uptake, choice, and efficacy of different CRC screening methods in women is dissimilar to that in men. The mortality benefit from FOBT, sigmoidoscopy, and protection from interval CRC by colonoscopy appears to be lower in women than men. A greater understanding of these gender idiosyncrasies will facilitate an personalized L. Chacko Department of Gastroenterology and Hepatology, Denver Veterans Affairs Medical Center, Denver, CO, USA C. Macaron
C. A. Burke (&) Department of Gastroenterology and Hepatology, Cleveland Clinic, Desk A 30, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected]

approach to CRC prevention and should ultimately lead to a reduced burden of disease. Keywords Colorectal cancer
Colorectal cancer prevention
Colorectal cancer screening
Colorectal cancer and women

Introduction The United States Census Bureau estimates that females comprise 51 % of the US population. Women have a longer life expectancy than men and represent an increasingly greater proportion of the population: 57 % of Americans over age 65, and 66 % of those aged 85 years and older. In 2000, white females comprised nearly 70 % of the female population. It is projected that in 2050, they will no longer be the majority (46 %) and nearly one-third of females will be Hispanic, 12 % will be Black, and 8 % will be Asian [1]. As this demographic shift occurs, a greater proportion of females in the USA are anticipated to be the head of household, live below the poverty level, and experience food insecurity which magnifies disparities in health, nutrition, uptake of healthcare services, and ultimately, the risk of colorectal cancer (CRC). CRC is one of the most common cancers and cause of cancer deaths in American women, and the risk is significantly increased among individuals with low socioeconomic status [2]. Over the past 30 years, a substantial decline has been noted in the incidence of and mortality from CRC in women, albeit less than the benefit observed in men (Fig. 1). The use of CRC screening and removal of adenomas are believed to be the leading contributors to the decline. The uptake of screening reported by women is lower (58 %) compared to men (60 %), with the lowest

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Dig Dis Sci Fig. 1 Time trends of colorectal cancer incidence and mortality in men and women in the USA. Modified from The website of the National Cancer Institute (http://www.cancer. gov)

rates in Asians (46 %) and Hispanics (47 %) [3]. Identified barriers to CRC screening include cost, access to health care, ethnicity and cultural preferences, recent immigration, and younger age, and must be obviated particularly in women as the demography of the female population shifts. Risk Factors for CRC Demographics The cumulative lifetime risk of CRC is similar in men (1 in 20) and women (1 in 22) [4]. While the incidence of and death from CRC is lower in women than men, it varies by ethnicity. Hispanic women are at lowest risk and black women experience the highest rates and is similar to rate in the white male population [3].

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Adenomas The majority of sporadic CRC arise from adenomatous polyps. Advancing age is the greatest risk of the development of adenomas and CRC. Women have a significantly lower risk of conventional adenomatous neoplasia than men [5–10]. Consistent data demonstrate up to a twofold higher prevalence of both non-advanced adenomas and advanced neoplasia in men compared to women [7, 9]. The prevalence of adenomas, advanced adenomas (AA), and CRC in 44,350 individuals undergoing screening colonoscopy in Austria was significantly higher, and the number needed to screen (NNS) to detect each lesion was significantly lower, among men compared with women in every age group [10]. The NNS for the detection of AA and CRC was similar in men aged 50–54 years and women aged

Dig Dis Sci Fig. 2 CRC incidence and mortality in men and women around the world. Modified from Ferlay et al. [148]

60–64. Similar results were noted in a screening colonoscopy program of 50,148 participants in Poland [5]. The strength of evidence supporting the age-related gender disparity between men and women has been remarkably consistent in populations in numerous countries throughout the world (Fig. 2). Over a decade ago, it was shown that women reach equivalent levels of CRC and CRC mortality at an age 4–8 years older than men [6]. Recently, an analysis of screening colonoscopy in 2,185,153 German participants aged 55–75 years when adjusted for year of birth [9] reconfirmed that women reached equivalent rates of CRC and advanced neoplasia, at an age 3.4 and 6.9 years later than men, respectively. The cause for the male–female disparity in the agerelated prevalence of conventional adenomatous neoplasia, yet similar cumulative lifetime risk of CRC, is incompletely explained by female longevity. Gender differences in exposure and metabolism of hormones, lifestyle and

dietary factors, genetic and biologic variation, and the prevalence of CRC precursors are likely at play. Studies over the last decade analyzing data from the Clinical Outcomes Research Initiative (CORI) endoscopy database demonstrate that women are at greater risk than men of having purely right-sided polyps and tumors [8] including large ([9 mm) proximal polyps [11]. While the pathology of lesions cannot be ascertained by CORI, recent SEER data show that a greater proportion of CRC in women are located in the proximal colon (45 %) compared to men (36 %) and suggest that the lesions reported in CORI are of substantial clinical implications for women [12]. Methylation and Sessile Serrated Polyps There are substantial gender-related differences in the molecular biology of colonic neoplasia. In one study where the frequency and degree of methylation of two genes was

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analyzed by age, gender, and location in the colon, no consistent pattern of promoter methylation of hMLH1 and MGMT was seen in the normal mucosa or CRC in men, while a striking difference was noted in women, particularly in the right colon [13]. Hypermethylation at multiple CpG islands (CIMP), evidence of microsatellite instability (MSI-H), and concomitant loss of hMLH1 are more common in colon cancers from female patients and are often the molecular features of tumors found in the proximal colon [14–16]. A recent systematic review and meta-analysis of nearly 12,000 patients with colorectal cancer investigated the association of the BRAF V600E mutation and clinicopathological features of CRC. BRAF V600E mutation was associated with female gender, proximal colon, CIMP, and MLH1 methylation [17]. These are similar molecular features to those that occur in sessile serrated polyps (SSP). Numerous studies have documented the association between SSP and female gender [18–21]. In an analysis of over 290,000 colon specimens in 179,111 patients, women were overrepresented among patients with SSP and comprised 53 % of the patients with an SSP without dysplasia, 57 % of the SSP with low-grade dysplasia (SSP-LGD), 69 % of the SSP with high-grade dysplasia (SSP-HGD), and 76 % of the patients with an adenocarcinoma arising in an SSP (SSP-CA) [21]. In the study, among patients with an SSP, women were at a nearly twofold higher risk of developing SSP-HGD and a threefold risk of SSP-CA. The median age of patients with an SSP is 62 years, SSP-LGD 66 years, and SSP-CA 76 years [18, 21]. Smoking Smoking is a significant risk factor for colorectal neoplasia including SSP, adenomas, high-risk adenomas, and CRC [18, 22–26]. Although much of the early data supported a stronger association between smoking and CRC in men, more recent data show that female smokers show evidence of greater susceptible than men including the development of SSP [18], proximal CRC, earlier age of onset, and death from CRC [22, 23, 27, 28]. A meta-analysis of cigarette smoking and adenomas found a twofold increased risk of female current and ever smokers versus never smokers [24]. Another meta-analysis of smoking and CRC demonstrated a positive association between smoking and CRC incidence in women who were former or ever smokers and an increase in CRC mortality in current, former and ever female smokers [25]. A 20 % increased risk of death from CRC was recently demonstrated in female ever versus never smokers [22]. The risk of death from proximal CRC in this cohort was 50 % higher than in female never smokers. When compared to male smokers, one study identified a slightly increased risk of CRC mortality in

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female smokers [27]. It has been suggested that it may take 35 years for the induction period of smoking-related CRC [26] and given that women did not start smoking in substantial numbers until the 1950s, a lag time effect would be expected. Through multiple studies, the biologic and molecular characteristics of smoking-related colon cancer in women have emerged. They tend to be MSI-H, CIMP positive, and BRAF mutated with a location in the proximal colon [23, 29–31]. This indicates that smoking may exert its greatest effect on CRC in women via the serrated pathway of carcinogenesis as these characteristics are closely associated with this pathway. Obesity Obesity as measured by body mass index (BMI) or central adiposity (waist circumference and waist-to-hip ratio) has been linked in numerous studies and meta-analyses to a higher risk of colonic neoplasia. Studies have shown a consistent association with body fatness and colon cancer in men, but the association has been inconsistent and less strong in women [32–35]. In contrast, measures of central adiposity (waist circumference, waist-to-hip ratio) have been shown in some studies to be more strongly associated with colon cancer than BMI in women [33, 36]. Given that men are more likely to develop central adiposity, this association could provide a partial explanation for the increased incidence of CRC in men compared to women. The effect of obesity on colonic adenomas in a recent meta-analysis showed that a BMI C 25 kg/m2 was associated with an increased prevalence of adenomas in both women (?16 %) and men (?19 %) without a significant difference noted between the genders [37]. No impact of obesity was noted on the incidence or post-polypectomy recurrence of adenomas when adjusted for many important variables in the female participants in the prostate, lung, colorectal, and ovarian cancer screening trial which randomized participants to flexible sigmoidoscopy screening [38]. The inconsistency in the data on obesity as a risk factor for colorectal neoplasia in women is likely related to the complex interaction between estrogen (including menopausal status and hormone replacement therapy), body fat distribution, and hormonal status of colorectal tumors. Height Height has been evaluated extensively regarding its impact on colon cancer risk. The majority of data support an association, and potential explanations include the association between height and colon length (and increased number of colonic cells), higher energy intake during childhood, and higher levels of IGF-1 [36, 39].

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Physical Activity In some studies, physical activity has been associated with a lower risk of colon cancer and colonic adenomas in women and may be protective by decreasing intestinal transit time, lowering insulin levels, altering prostaglandin level, and improving immune function [40, 41].

compared to women eating one serving per day or week, respectively [49]. No effect of vegetable intake was observed. In one intervention trial, simply lowering dietary fat was not shown to reduce the risk of colon or rectal cancer in postmenopausal women; however, self-reported adenomas were reduced [50]. Diabetes

Diet The impact of diet on CRC has been explored in a number of studies and reviewed recently [42]. Total caloric and red and processed meat intake have been associated with an increased risk of CRC in men and inconsistently associated with risk in women. In the Nurses Health Study (NHS) [43], women who reported the highest consumption of fat ([82 vs. \58 g/day), primarily of animal origin, or ate beef, pork, or lamb daily (vs.\once per month) were at a two and two and one-half-fold higher risk of colon cancer, respectively. Processed meats and liver were also significantly associated with increased risk, whereas diets of fish and chicken without skin were related to a decreased risk. In one study, after adjustment for non-dietary factors, no significant risk from the intake of red or processed meat was found while increasing fish and poultry intake was protective in women [44]. In a screening colonoscopy study in women, high intake of red meat, pan-fried meat, and the heterocyclic amine MeIQx (a meat mutagen) were associated with an increased risk of colorectal adenomas [45]. Diets characterized by higher meat, fish, and sweetened beverage intake and lower coffee, whole grain and high-fat dairy intake are associated with elevated C-peptide, a marker of insulin, and an increased risk of CRC in women [46]. The effect was notable for colon but not rectal cancer and particularly in overweight or sedentary women. In another analysis from that study, women who responded ‘‘I eat anything I want, anytime I want’’ had a nearly 30 % increased risk of CRC, after adjusting for known risk factors of CRC [47]. In addition, these women were found to have higher fasting plasma levels of insulin and C-peptide. The association of dietary factors and colorectal adenomas was also evaluated in the Black Women’s Health Study [48]. An inverse association was noted for the risk of adenomas in women who reported eating the highest levels of a ‘‘prudent’’ diet (higher intake of vegetables, fruits, whole grains, low-fat dairy, fish, and poultry) while women who ate the highest levels of a ‘‘Western’’ diet (higher intake of refined grains, high-fat dairy, meat and processed meat, eggs, butter, sweets, etc.) had the highest risk of adenomas. A decreased risk of distal adenomas was observed in women undergoing colonoscopy or sigmoidoscopy in the NHS who reported eating five or more servings of fruit a day or four or more servings of legumes per week

Insulin is involved in pathways activating insulin-like growth factor (IGF)-I signaling and inhibiting IGF binding proteins which can increase cell proliferation and inhibit apoptosis. Not surprisingly, diabetes mellitus (DM) is associated with an increased risk of CRC in men and women. In a large meta-analysis, women with DM had a 30 % increased risk of CRC compared to non-diabetic women [51–54]. The effect of DM is inconsistent in regard to the association with adenomas [55, 56]. CRC Screening A number of survey tools and studies have evaluated gender differences in compliance with CRC screening. Much of the data are self-reported with the Behavioral Risk Factor Surveillance System (BRFSS) and the National Health Interview Survey (NHIS) serving as the largest sources in the U SA. Screening Rates In general, women have a higher utilization of healthcare services, and preventive services in particular, compared to men. While the overall rates of CRC screening are increasing in women, they slightly lag behind reported rates in men [3]. As might be expected, women who are compliant with breast and cervical cancer screening have been shown to be more compliant with CRC screening [57]. A panel of CRC screening modalities has been endorsed by the United States Preventive Services Task Force including fecal occult blood testing (FOBT), flexible sigmoidoscopy, and colonoscopy [58], but colonoscopy is the most commonly used screening test in the USA in both men and women [59]. Its use for screening has increased threefold in women in the last decade [60]. Interestingly, and in contrast to men, randomized trials show women are more likely to adhere to fecal immunochemical testing than colonoscopy as their screening test [61, 62]. Predictors/Barriers to Screening There are a variety of factors which have been linked to participate in CRC screening.

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Provider Recommendation One of the strongest factors associated with compliance is a physician’s recommendation for screening [57]. There are some data that women are referred for CRC screening less often than men and less consistently than for mammogram and Papanicolaou smears [57, 59, 63]. In addition to gender, participation is also impacted by age, level of education, health insurance, socioeconomic and marital status, race, recent immigration, regular access to health care [3, 64]. Perceptions of Screening Tests A number of studies have attempted to explore women’s perceptions about and potential barriers to CRC screening. Concerns about embarrassment, fear, anxiety and vulnerability, test inconvenience, and bowel preparation have been shown to be more pronounced in women than men [65–67]. Some women are more likely to have a preference for a female endoscopist [65, 66, 68] with a subset being willing to wait longer and pay more for their procedure in order to have it performed by a woman [66–68]. Although women cite a preference for a female endoscopist, some studies show the availability of one is not associated with an increase in screening compliance with colonoscopy [69, 70] even when offered at the time of invitation or scheduling of the examination in an outreach program [70]. Body Weight Body weight has been evaluated as a factor in adherence to CRC screening. Increasing weight has been inversely associated with screening adherence in women but either positively or not associated in men [71–73]. One study assessed the impact of obesity and race on CRC screening behavior in women utilizing the 2005 NHIS database [74]. Overall, screening rates were higher in white than black women and the relationship between obesity and reported adherence differed by race for any screening test and colonoscopy but not for FOBT. Obese white women had a 33 % lower adjusted colonoscopy rate than nonobese white women and also had the lowest colonoscopy use of all women. Interestingly, obese African-American women had a higher colonoscopy rate than non-obese African-American women. The rationale for these differences is unclear but may be due to racial differences in body image. Context of Screening Recommendation The positive impact of a provider recommendation for CRC screening on adherence is well established. The delivery of the message is also of key importance [75]. A well-known female television celebrity, Katie Couric, capped off a week-long CRC awareness campaign with an on-air colonoscopy in 2000 [76]. A significant increase in the number of colonoscopies performed each month appeared immediately and was sustained for the duration of the

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analysis. There was a trend for more uptake of colonoscopy in women than men which may be related to women identifying with someone of their own gender or a reduced perception that colon cancer is a man’s disease. Efficacy of Screening There is some suggestion that the efficacy of different CRC screening methods in women is dissimilar to their effect in men. In part differences could be related to technical issues or biology with the decreased prevalence of conventional adenomas and increased proportion of SSP with a predilection for proximal location in women compared to men. In the 30-year follow-up of the Minnesota Colon Cancer Control Study, both annual and biennial FOBT significantly reduced CRC mortality in men, but no benefit was observed in women randomized to the biennial FOBT arm or in women less than 60 years of age [77]. Population data show a reduction in the use of flexible sigmoidoscopy for CRC screening. However, over the last 5 years strong data from randomized controlled trials have demonstrated its benefit for the prevention of CRC in men. Inconsistent results have been observed for its benefit in women. In the PLCO trial, the incidence reduction of CRC in women randomized to flexible sigmoidoscopy was only half that observed in men (14 vs. 27 %). Similarly, CRC mortality was reduced 34 % in men, while no reduction was noted in women [78]. In contrast, data from the Italian flexible sigmoidoscopy trial (SCORE) showed no overall mortality benefit, but a reduction in CRC incidence was detected, and it was greater in women than men [79]. In the UK flexible sigmoidoscopy trial, both CRC cancer incidence and death were reduced by sigmoidoscopy and no significant differences in the outcomes were seen between men and women [80]. It is possible that differences in the populations studied, quality and extent of sigmoidoscopy and gender-related differences in the biology, or location of neoplasia accounted for the variable results of flexible sigmoidoscopy in women versus men. Studies have also assessed the value of distal findings on sigmoidoscopy to predict proximal neoplasia and thus patients who may benefit from colonoscopy. Distal adenomas are associated with an increased risk of proximal adenomatous neoplasia in both men and women, and colonoscopy is recommended in individuals with an adenoma detected on screening sigmoidoscopy. The implication of a negative sigmoidoscopy on the risk of proximal neoplasia has been shown to be gender specific, however. In one study of over 10,000 individuals without distal adenomas, the prevalence of proximal advanced neoplasia in men was threefold higher than women. The yield of colonoscopy for advanced neoplasia beyond what sigmoidoscopy would reveal in those younger than

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70 years was 0.86 % in women and 1.5 % in men and translated into nearly a threefold higher number needed to screen to detect advanced proximal neoplasia in women than in men [81]. In contrast, in a study performed in 1,463 women [82], which was designed similar to the VA Cooperative Study 380 screening colonoscopy study which was composed of 97 % male veterans [83], the prevalence of advanced proximal neoplasia in women without and with distal neoplasia was 3.4 and 3.2 %, respectively. When compared to men in the VA Cooperative Study 380, the diagnostic yield of sigmoidoscopy for advanced neoplasia was only 35.2 % in women compared to 66.3 % of men. The cause of these inconsistencies are unknown but could be related to the differences in populations studied, associated risk factors, completeness and quality of the examination, and propensity for women to have a higher proportion of right-sided advanced lesions than men. Several studies have found that the depth of insertion of flexible sigmoidoscopy in women is substantially less, and they are less likely to have a complete exam compared to men [84, 85]. The use of an upper endoscope for flexible sigmoidoscopy in women is associated with less pain than a standard sigmoidoscope, and reduction in pain is associated with a greater depth of insertion [86]. The use of screening colonoscopy has increased in the last two decades and is the leading CRC screening modality utilized by both men and women in the USA. Substantial cohort and case control data demonstrate a sustained reduction in incident CRC for up to 20 years after a negative complete procedure [87–90]. Unfortunately, some data suggest the strength of the protection from colonoscopy on interval CRC appears to be lower in women than men. A variety of factors has been associated with interval cancer occurrence including the specialty of the endoscopist, practice setting where the procedure is performed, the presence of diverticulosis, adenoma detection rate (ADR), and completeness of exam. Female gender has also been shown to be a predictor of interval cancer [91–94], and in some studies, women were up to 34 % more likely to have an interval CRC than men [93]. In women, but not men, a history of previous abdominal or pelvic surgery was shown to be an independent predictor of interval cancer [94]. In a case–control study of interval CRC after negative colonoscopy in Germany, a more than fourfold increase in the risk of interval cancers was found in women with a previous incomplete examination, while no association was seen in men [91]. There is also evidence that the performance of colonoscopy is more difficult in women [10, 95–97] particularly those who have undergone an abdominal hysterectomy [95, 98, 99]. Lower completion rates [10,

95–97], increased time to cecum [95], more looping [99], and a higher pain level and sedation needs have been noted in women compared to men [5, 10, 99]. The use of a pediatric colonoscope has been shown to increase cecal intubation in women with hysterectomies [100]. Several studies have sought to determine whether there are any clear anatomic differences between male and female colons. A variety of methods have been used to compare the length of the colon in men and women [101–103]. Women have longer colons than men, particularly in the transverse colon, despite their smaller stature. Women have greater redundancy of the colon defined as sagging of the transverse colon into the true pelvis [101]. Three-dimensional magnetic imaging during colonoscopy has shown that loop formation is more likely to occur in women than men [99, 102]. These colon-related factors in addition to the anatomic factors of decreased abdominal adiposity and musculature, and a deeper and more rounded pelvis in women compared to men likely all account for the technical challenge in performing colonoscopy in women. As such, they may potentially impact adequate detection rates of neoplasia and lead to interval CRC development in women. Gender/Racial Interactions Gender and racial differences in the biology of colorectal neoplasia may contribute to interval CRC. Black women suffer the highest rates of advanced neoplasia including CRC when compared to women of other ethnicities. Data from the CORI database were utilized to determine the prevalence and location of large polyps ([9 mm) in over 85,000 black and white men and women undergoing screening colonoscopy [11]. White women had the lowest rates of large lesions. Black women had a 60 % greater risk compared to white women, and only a borderline difference in prevalence was seen between black women and men. Also of note, a higher prevalence of large, proximal polyps was seen in blacks and was most striking for black women compared with white women. These racial disparities between women were confirmed in a screening colonoscopy study in approximately 3,000 women [104]. The prevalence of adenomas was least frequent in whites, 16 %, followed by 19 % in Hispanics and 23 % in blacks. Racial disparity has also been demonstrated in the molecular biology of CRC. Recent data from a population-based study demonstrate the frequency of MSI-H colon cancer in blacks is half of the prevalence in whites [105]. The study also demonstrated microsatellite stable cancers in blacks were associated with younger age, female gender, and proximal location. Other studies have confirmed that proximal colon cancer rates are higher in females than males, particularly for black individuals less than age 40 [106]. This has

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important implications for the benefit of colonoscopy over sigmoidoscopy for women, particularly black women. Dietary and Chemoprevention NSAIDs Follow-up of individuals with long-term aspirin use has shown a decrease in the incidence and mortality from CRC. Much of the date is obtained from randomized studies assessing daily aspirin use on cardiovascular end points [107, 108]. Studies specifically in women have revealed similar findings. In the NHS [109], a 44 % risk reduction in colon and rectal cancers was found after 20 years in women who reported 2 or more aspirin tablets per week. In the Women’s Health Study (WHS), women were randomized to 100 mg of aspirin every other day for a mean duration of use of 9 years. At 18 years of follow-up, the combined intervention and post-trial incidence of CRC was reduced 20 % [110]. When the analysis was restricted to the post-trial observation period, the reduction was 42 %. Similar to previous studies [107], a stronger protection against proximal colon cancer was noted. As might be expected, an increase in gastrointestinal bleeding (14 %) and peptic ulcers (17 %) was reported in those randomized to aspirin. In the Iowa women’s study, postmenopausal women reporting the use of aspirin six or more times weekly and non-aspirin NSAIDs two to five times a week had a reduced risk of colon cancer by 24 and 37 %, respectively [111]. The strongest association was noted for proximal colon cancer by women who used aspirin or NSAIDS two or more times weekly. A meta-analysis of randomized trials of aspirin for adenoma prevention which included over 1,000 women showed a decreased risk of recurrence of 17 % for any adenoma and 28 % for advanced adenomas [112]. The longterm effect of regular low-dose aspirin on colorectal cancer prevention is undeniable, yet the dose, risk, and harms are not fully established. Folic Acid Supportive evidence for the role of folic acid in CRC prevention derives from multiple observational studies [113–115]. In the NHS [113], a 75 % risk reduction in colon cancer was observed in women who used multivitamins containing folic acid for at least 15 years although the protective effect was not seen in rectal cancer. In addition to duration of use, a dose–response effect was seen with a 30 % lower risk of colon cancer in women with an intake greater than 400 lg/day. More recently, the protective effect of folic acid has been questioned [116]. Approximately 1,000 individuals (36 % women) randomized to 1 mg/day of folic acid daily for 3 years found no

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benefit of folate on metachronous adenomas on colonoscopy. At the second post-polypectomy colonoscopy interval after an additional 3–5 years of treatment, folic acidexposed patients were 67 % more likely to have at least one advanced adenoma and more than twofold more likely to have three or more adenomas. In addition, a higher rate of non-colorectal cancer was observed in the patients randomized to folic acid. Data from the Iowa Women’s Health study [117] showed an increase in all cause mortality in elderly women using multivitamins and folic acid supplementation. The inconsistent evidence regarding folate has raised concerns over a possible dual carcinogenic effect of folic acid, protecting normal mucosa while enhancing the growth of preexisting lesions. Therefore, folic acid is not recommended as a CRC chemopreventive agent. Fiber Although studies with metabolic end points [118, 119] showed that wheat-bran fiber reduces fecal bile acid concentrations and absorbs fecal carcinogens, and no protective effect of dietary fiber against CRC or adenoma was observed in the NHS after 16 years of follow-up [120]. Similarly, no protective effect of dietary or supplemental fiber against CRC or adenomas has been observed in multiple randomized controlled studies [121–124]. Although observational and intervention studies failed to show a role in preventing CRC and adenomas with fiber, there are other health benefits to eating diet high in fiber, fruits, and vegetables. Antioxidants Epidemiologic studies and intervention trials have assessed the role of antioxidants in CRC or adenoma prevention with inconsistent results [125–127]. An inverse association between colon cancer risk and vitamin E intake was found in women under age of 60 [125], but no benefit was observed in another intervention trial [127]. Supplementation with b-carotene or vitamins C, or E had no protective effect against recurrent colorectal adenomas 1–4 years after baselie adenomas were cleared [126]. At present, there is insufficient evidence to support the use of supplementary antioxidants to reduce the risk of CRC. Furthermore, there is evidence indicating that certain oxidants such as vitamin E and b-carotene are harmful and associated with an increase in mortality [128, 129]. Calcium/Vitamin D Calcium supplements are commonly used for their beneficial effects on bone. The effects of dietary or supplementary calcium and vitamin D on the risk of colorectal

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neoplasia are inconsistent or indicate weak inverse associations. No effect against CRC was observed in the NHS [130], WHI [131], and WHS [132] studies. Conversely, men and women randomized to 1,200 mg of supplemental elemental calcium daily for 3 years in the Calcium Polyp Prevention Study [133] showed a 15 % risk reduction in metachronous adenomas. There also may be risks associated with calcium supplementation in women. In a 5-year randomized trial of 1,000 mg of elemental calcium supplementation in healthy postmenopausal women designed to assess its effects of fractures and bone density, calcium supplementation was associated with an upward trend in cardiovascular event rates [134]. In a pooled analysis of 11 randomized trials including around 12,000 participants, calcium supplementation at 500 mg or greater daily was associated with a 30 % increased risk of myocardial infarction [135]. The majority of the studies included in the analysis was performed in postmenopausal women for the assessment of bone health and fracture risk and excluded trials which utilized a combination of vitamin D and calcium supplementation. The inconsistent or modest benefit of calcium on the prevention of colorectal neoplasia and potential cardiovascular harm does not support a role for its use in primary prevention of CRC or secondary prevention of adenomas. Hormone Replacement Therapy Sex hormones are believed to be one of the factors that account for the gender difference in the prevalence of conventional adenomas and CRC. Estrogens are thought to be protective by a number of different mechanisms. The estrogen receptor gene is expressed in colonic mucosa and has been shown to suppress tumor growth [136], while its expression is diminished in malignant colon tissue [137]. Exogenous estrogen decreases serum levels of insulin-like growth factor (IGF-1) [138, 139] and reduces bile acid production [140, 141], known mitogens in colorectal carcinogenesis. In the NHS, postmenopausal women who were current users of hormone replacement (75 % estrogen alone) were observed to have a 35 % reduction in colorectal cancer and a 26 % reduction in large distal adenomas compared to nonusers [142]. Data from the WHI confirmed a protective effect of estrogen plus progestin (E ? P), but not estrogen alone, versus placebo, against CRC in postmenopausal women [143]. During the 5-year intervention phase of the trial, a 38 % reduction in incidence of CRC was observed. Surprisingly, the CRCs diagnosed in the E ? P arm were more likely to be advanced [144, 145]. Extended follow-up of the WHI trial has recently been published [143, 144], and no reduction in CRC during the cumulative or post-intervention phase was noted in either arm. Similarly, the heart and estrogen/progestin

replacement study hormone replacement therapy in postmenopausal women reported no protective effect against colon cancer after 6.8 years of follow-up [146]. Taken together, these findings do not support an appreciable longterm benefit of hormone replacement therapy in CRC chemoprevention in postmenopausal women. Combinations The cost-effectiveness of combining aspirin and/or calcium with colonoscopy to prevent CRC has been studied in a Markov simulation [147]. Even at 50 % compliance with colonoscopy, it alone was predicted to be more effective and less costly than no screening. Colonoscopy with aspirin or calcium was the next most cost-effective strategy with an incremental cost-effectiveness ratio per life year saved of $12,950 for aspirin and $13,041 for calcium.

Conclusions As the third most commonly diagnosed cancer and third most common cause of cancer death in women in the USA, colon cancer remains a significant health issue for women. The ageadjusted incidence of conventional adenomas and advanced neoplasia is lower in women than men, yet the lifetime prevalence of CRC is similar between the genders. As summarized here, gender differences are recognized in the biology of CRC with women having proportionally greater proximal tumors, which are characterized by MSI-H and BRAF mutated, suggesting their development from SSP. Risk factors, including distribution of adiposity, hormonal status, and race, and issues surrounding screening, such as barriers, compliance, and efficacy, differ significantly by gender and within racial subsets of women. Technical challenges in the performance and quality of colonoscopy in women will need to be overcome to decrease the higher observed interval cancer development in women. In the era of personalized medicine, it is likely that the ultimate approach to colorectal cancer prevention will be individualized based upon the factors above and will not be ‘‘one size fits all’’ for either women or men.

Conflict of interest

None.

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