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Abstract

Breast cancer and endometrial cancer are the most common gynecologic malignancies of the postmenopausal period. As preventive medicine becomes the focus of interest, preventive oncology with special regard to these diseases will undoubtedly become a substantial part of the practicing oncologist's field of duties. The aim of this review is to summarize recommendations dealing with the risk assessment and prevention of breast and endometrial cancer. Obesity, the level of exercise and dietary factors are associated with breast cancer. The selective estrogen receptor modulators tamoxifen and raloxifen have both been shown to decrease the risk to the same extent. Patients at particularly high risk are being detected through the use of the Gail model, a well-known statistical model of risk. Other factors, such as breast density, the serum level of endogenous estrogen and the presence of single nucleotide polymorphisms, have to be taken into consideration.

Keywords

breast cancer chemoprevention endometrial cancer female health oncology postmenopausal prevention

In ancient China, medical advisors were paid for the prevention of diseases rather than their treatment. Today, patients indicate a genuine interest in preventive medicine, especially in awareness of the aging population. Preventive neurology becomes a social challenge with regard to the dramatically growing incidence of neurodegenerative disorders. Breast cancer and endometrial cancer are the leading gynecologic malignancies of the postmenopausal period and therefore modern medicine should increasingly engage in preventive oncology. Much of the effort should be directed toward preparing the medical staff and the scientific community for preventing diseases in addition to treating them. Lessons can be learned from preventive cardiology, especially with regard to the past few decades. Preventive cardiology, as well as preventive oncology, have gathered good clinical evidence showing that disease risk can be reduced by changing lifestyles and by engaging in chemopreventive strategies. Defining well-investigated risk factors allows for the assessment of patients at high risk. In these cases, more intensive healthcare management is justified.

Many postmenopausal patients would be grateful to receive more information from doctors regarding evidence-based recommendations for prevention, especially when they are cheap and easy to realize.

Preventive oncology: recommendations

Obesity

The first evidence that heavier women are at increased risk of breast cancer was obtained in the 1970s [1 –3]. Many subsequent studies investigating this issue have established important differences between pre- and postmenopausal women. In contrast to the premenopausal period, several case–control studies in postmenopausal women have shown an increase in breast cancer risk of approximately 40% for women whose BMI values are in the highest quartile or quintile. In prospective cohort studies, however, this increase in risk is more modest at approximately 20%. This association becomes stronger with increasing age and years after menopause [4,5]. Weight gain during adult life is also consistently associated with increased risk of postmenopausal breast cancer [6 –8]. Some studies have shown a stronger association between BMI and postmenopausal breast cancer risk in women who have never used hormone-replacement therapy (HRT) [9]. This finding is consistent with the hypothesis that the effect of obesity on breast cancer risk may be mediated by increased endogenous estrogen production. Most studies on breast cancer and obesity have been performed in developed countries, but of the few studies that have been carried out in less developed countries, the majority have produced similar findings [10]. Convincing evidence also exists for the role of obesity as risk factor for endometrial cancer. Case–control studies have reported a 200–400% linear increase in relative risk of developing endometrial cancer in individuals with a BMI above 25 kg/m². Cohort studies have also reported an increase in risk, although of smaller magnitude. Adult weight gain is an even stronger predictor of risk than weight measured before the clinical manifestation of endometrial cancer [11 –13].

The increase in cancer risk that is associated with excess body weight or increases in abdominal fat may be mediated by alterations in the metabolism of sex steroids, insulin and insulin-like growth factor (IGF) 1. Sex steroids are known to regulate the balance between cellular differentiation, proliferation and apoptosis, and may also favor the selective growth of preneoplastic and neoplastic cells [14].

In contrast to the strong evidence linking obesity and oncogenesis, only a few studies have addressed these biochemical mediators of obesity and the results are difficult to interpret because information on the cause of weight loss was mostly lacking or insufficient.

Central obesity, a hormonal profile with elevation of the endogenous estradiol and IGF1 serum concentrations, sedentary lifestyle and unopposed estrogen usage are high-risk factors for endometrial cancer and should be considered in preventive strategies against endometrial cancer.

Exercise

Promotion of physical activity seems to be effective for prevention of weight gain [15]. In addition, major benefits of physical activity, above and beyond weight control, are well known, including a decrease of all-cause mortality and incidences of cardiovascular diseases and diabetes.

It has been speculated that 30–60 min of physical activity reduces cancer risk independently of changes in body weight or BMI [16]. Thus, it has been estimated that 30–60 min of daily physical activity may reduce the risk of breast and endometrial cancer by 20–40%. Many epidemiological studies on physical activity and cancer risk are characterized by design limitations. However, these issues are mainly due to the difficulties involved in accurate assessment of physical activity. In the Nurse's Health Study (NHS), for example, physical activity was associated with a 20% reduced incidence of breast cancer among postmenopausal women [17].

In addition, physical activity after a breast cancer diagnosis may reduce the risk of death from this disease, as shown by Holmes et al. [18]. In the NHS, 2987 female registered nurses were diagnosed with stage I–III breast cancer. Among these women, a strong association between breast cancer mortality and the level of physical activity was found. This benefit of physical activity was particularly apparent among women with hormone-responsive tumors [18].

Dietary risk factors

The first major dietary findings of the NHS study were published in 1987 and demonstrated that moderate alcohol intake increased the risk of breast cancer independently of other diet components [17,19], which had not been addressed in previous studies. This increase in risk has been confirmed in many studies and alcohol intake remains the best-established dietary risk factor for breast cancer. Alcohol intake is also related to an increased risk of colon cancer [19,20]. Of note, alcohol reduces plasma and serum folate concentrations. A number of studies demonstrated an inverse association between folate intake and breast cancer incidence. This association was most evident among women who were considered ‘high risk due to their alcohol consumption of greater than 15 g – approximately one drink – per day [21]. Similarly, studies of plasma levels of folate revealed a significant reduction in breast cancer risk, particularly among women who consumed alcohol [22]. These data indicate that folate may be used as a preventive agent among women with regular alcohol consumption.

In a large study including more than 90,000 women aged 26–46 years with a median follow-up of 12 years [23], a strong association between red meat intake and the incidence of estrogen and/or progesterone receptor-positive breast cancer in premenopausal patients was described. Although there are no dietary intervention studies regarding red meat in the premenopausal area, this should be a future area of study because we have to live with our past and lifestyle before the menopause has consequences decades later.

The European Prospective Investigation into Cancer and Nutrition (EPIC) project aims to improve the scientific knowledge of nutritional factors involved in cancer. To date, 24,185 cancer cases have been identified in the follow-up of the cohort. The publications produced by each center can be consulted on the EPIC website [201]. Among initial findings concerning the associations between cancer and dietary factors, one of the most important results is a protective effect of high fiber intake and fish consumption against colorectal cancer, while high red and processed meat intake increase the risk. Regarding lung cancer, the first analyses found a protective effect of fruit intake but no association with vegetable consumption. No association was observed between vegetables and fruit intake and the risk of prostate cancer or breast cancer. Finally, data from Cambridge (UK) point to an interesting result regarding breast cancer: no association was observed with saturated fat intake measured by food-frequency questionnaire but, according to the food diary, a daily intake of 35 g doubles the risk of breast cancer compared with women with daily intake of 10 g or less [24].

Chemoprevention

In 1998, the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial showed a substantial reduction of breast cancers in women at increased risk, as assessed by the Gail model, who received 5 years of tamoxifen compared with placebo [25,26]. This trial was recently updated with a median follow-up of 7 years and continues to show a significant reduction in breast cancer incidence in those women who received tamoxifen, regardless of age [27]. This risk reduction is at the expense of an increase in endometrial cancer in women older than 50 years and of thromboembolic events. The results from three other prevention trials in which women received tamoxifen have not shown such impressive results for several possible reasons, such as including different risk populations [28 –30]. Nonetheless, an analysis combining all the chemoprevention trials shows a 38% reduction in the incidence of breast cancer in patients treated with tamoxifen (95% confidence interval [CI]: 28–46) [31].

The selective estrogen receptor modulator raloxifen has been approved for the prevention and treatment of osteoporosis in postmenopausal women. The incidence of breast cancer in osteoporosis trials was substantially reduced in patients treated with raloxifen compared with placebo [32]. Raloxifene, unlike tamoxifen, does not have estrogen-agonistic effects on the uterus in rodents [33], and did not result in endometrial thickening in osteoporosis trials [34]. These findings led to the second NSABP prevention trial, the Study of Tamoxifen and Raloxifen (STAR).

The STAR trial enroled 19,747 postmenopausal women (mean age 58.8 years) with a 5-year Gail risk greater than 1.67%, who were randomized to receive either tamoxifen 20 mg or raloxifen 60 mg for 5 years. Of the 327 invasive breast cancers diagnosed, 163 and 168 invasive breast cancers were observed in women assigned to tamoxifen and raloxifen, respectively. Therefore, it was concluded that raloxifen is equivalent to tamoxifen. However, the side-effect profile favored raloxifen in that there were 36 and 23 cases of uterine cancer with tamoxifen and raloxifen, respectively, and fewer hysterectomies and thromboembolic events with raloxifen. Similarly, there were fewer cataracts and cataract surgeries noted in women taking raloxifen. The number of osteoporotic fractures was equivalent in both groups [35].

The cited studies also have limitations: lack of survival data, premature closure of the P1 trial with no survival data and long-term side effects. Currently running prevention trials, such as the International Breast Cancer Intervention Study (IBIS) II trial, still have a placebo-control arm.

Identification of risk factors for cancer prevention in postmenopausal women

The Gail model

A woman's risk of developing breast cancer within 5 years may be quantified by the Gail model, a validated mathematical model, which includes factors such as age, previous breast disease, nulliparity and family history of breast cancer [36]. The Gail model estimates the probability of an individual of a given age and set of risk factors developing invasive or in situ breast cancer over a specific interval. This was developed using data from the 284,780 women in a large case-control study, the Breast Cancer Detection Demonstration Project (BCDDP). Women in the BCDDP were predominantly Caucasian, between 35 and 79 years of age and underwent an annual mammogram. The Gail model includes risk factors that were major predictors of risk in the BCDDP and was derived from an unconditional logistical regression analysis. Risk factors include age, age at menarche, age at first live birth or nulliparity, the number of previous breast biopsies and whether any of the biopsies showed atypical hyperplasia, and the number of first-degree relatives (mother, sister or daughter) with breast cancer [37,38]. Another model was developed by Claus et al. using age-specific incidence data of breast cancer among the first- and second degree-relatives of 4730 Caucasian women with breast cancer and 4688 Caucasian controls aged between 20 and 54 years from the Cancer and Steroid Hormone Study [39].

The A 1 Tyrer–Cuzick model:

The recently published Tyrer–Cuzick model incorporates the Baye' theorem to calculate the mutation probability and then refines the calculation by maximum likelihood estimations for the relative risks of individual risk factors, such as age at menopause and menarche, weight, height, age, use of hormonal replacement therapy and previous benign breast biopsies. It is used as risk-assessment tool within the actual IBIS II study.

This model uses not only segregation analysis based on the existence of the known BRCA1 and BRCA2 mutation, but also an unknown predisposing gene, and incorporates individual risk factors by maximum likelihood calculations. This is, on the one hand, a strength of the model; on the other hand, risk estimates based on the mutation status may be too high as the role of an unknown predisposing gene is not described by clear frequency and penetrance data. Regarding the individual factors, it remains unclear whether parameters such as age at first birth or age at menarche and menopause vary according to BRCA1 and BRCA2 status [40].

Breast density

Approximately 50 studies have suggested that high breast density – in other words, relatively little fat and a high amount of connective tissue in the breast compared with the age-specific median – increases a woman's risk of breast cancer, and current estimates put the increase at four- to sixfold. Only two other traits are known to increase risk further: age and harboring a mutated allele of the breast cancer susceptibility genes BRCA1 or -2. Despite the consistent connection between breast density and cancer, fundamental biological questions remain [41]. It is unknown why an increased breast density increases the likelihood of breast cancer and how it modulates an individual woman's cancer risk. Also, it is unknown whether decreasing a woman's breast density will lower her chance of cancer.

The Breast Cancer Detection Demonstration Project [42] and the Canadian National Breast Screening Study [43] have shown that women with more than 75% increased breast density on mammography have an approximately fivefold increased risk of developing breast cancer over women with less than 5% increased breast density [44]. Both pre- and postmenopausal nulliparous women have, in general, an increased breast density [45] and therefore they may be at an increased risk of developing breast cancer. Nulliparity and high breast density seem to act synergistically since the breast cancer risk increases to sevenfold when they are both present [46]. It has also been shown that HRT users are more than twice as likely to have high-risk increased breast density patterns on mammography in comparison with nonusers [47].

The association between mammographic density and the risk of detection of breast cancer was published recently [48]. Extensive mammographic density is strongly associated with the risk of breast cancer detected by screening or between screening tests. A substantial fraction of breast cancers can be attributed to this risk factor.

Endogenous estrogen

After the menopause, the most important endogenous sources of estradiol synthesis are adipocytes and breast glands [49]. Therefore, it seems understandable that hypersynthesis of postmenopausal estrogen is a risk factor for endocrine-related cancers. Endogenous estrogen was evaluated for its impact on breast cancer risk in postmenopausal women in a quantitative review of 29 studies [50]. The six prospective studies showed a 15% higher serum estradiol concentration in breast cancer cases than in noncase controls; the case–control studies yielded similar differences in mean estrogen levels, although there was significant heterogeneity in the results. In a reanalysis of nine prospective studies addressing exposure to endogenous sources of estrogen, the risk of breast cancer was found to increase in a statistically significant manner with increasing serum concentrations of several sex hormones, including total, free and non-sex-hormone-binding globulin-bound estradiol [51]. Additional prospective studies support this association between higher serum levels of estrogen and increased breast cancer risk in postmenopausal women [52 –54]. Furthermore, the fact that the most widely acknowledged risk factors for sporadic breast cancer (including age, early menarche [55,56], older age of menopause [56,57], nulliparity [56], older age at first live birth [56 –59] and postmenopausal obesity [7]) are believed to reflect cumulative exposure of breast epithelium to estrogen over time is in agreement with these epidemiologic observations [51,60].

C/1 Hormone replacement therapy

Breast cancer risk increases with estrogen–progestin therapy (EPT) use beyond 5 years. In absolute terms, this increased risk was rare in the WHI, being four to six additional invasive cancers per 10,000 women per year who used EPT for 5 years or more. Studies have not clarified whether the risk differs between continuous or sequential use of progestogen. Women in the estrogen therapy (ET) arm of the WHI demonstrated no increase in risk of breast cancer after an average of 7.1 years of use, with eight fewer cases of invasive breast cancer per 10,000 women per year of ET use.

HRT should not be prescribed endemically. Individualization is also a challenge in this area. Several questions must be answered before starting HRT, which was not emphasized in the past: is there really a need for hormones in a given patient according their symptoms, which hormone should be prescribed (estrogen, progesteron, androgens) in which individualized dosage and when should it stopped. Estrogen replacement therapy was overdosed in the past and scientific trial with the lowest steroid dosage that is necessary for replacement should be performed.

Single nucleotide polymorphisms

Serum sexual steroid concentration does not reflect the tissue-specific hormone level, which is more influenced by the genetic variability of enzymes, synthesizing or metabolizing sexual steroids. Single nucleotide polymorphism diagnosis may therefore become a powerful tool for preventive oncology [61].

An analysis of 34 polymorphisms in 18 different genes, described in more than one breast cancer study, whenever possible with pooled analysis, showed an association with breast cancer for 13 polymorphisms in ten genes [61]. The HRAS1 gene encompasses four exons flanked by a variable tandem region repeat at the 3’ end [62,63]. This minisatellite locus is composed of four common alleles (94% of the white population) and dozens of variants, the so-called intermediate and rare alleles [64]. Each variant allele is derived from the common allele nearest to it in size [65]. The HRAS1 polymorphism was examined in 13 studies [66 –78]. Positive odds ratios (ORs) were detected in all studies, five of which reached significance [66,71,75,76,78] with ORs of 2:7.

The cytochrome P450 (CYP) 1B1 enzyme exceeds other p450 enzymes in both estrogen hydroxylation activity and expression in breast tissue [79]. Four polymorphisms have been described in this gene and all variants have higher hydroxylation activity [79]. These variant alleles may be associated with changes in estrogen metabolism and therefore breast cancer risk. Three of these polymorphisms were examined in breast cancer patients and controls. The codon 432 polymorphism was examined in three studies [80 –82]. Large differences in variant allele frequencies were found between different populations, with the variant allele frequency ranging from 0.15 to 0.68. When all studies were combined, a pooled analysis found no association between the codon 432 polymorphism and breast cancer. One study examining a CYP1B1 codon 119 polymorphism detected an association with an increased breast cancer risk in women heterozygous for the variant allele (OR: 1.62; 95% CI: 1.15–2.29) [81]. However, in women homozygous for the variant allele, a nonsignificant decrease in risk was found (OR: 0.6; 95% CI: 0.11–3.31). No association with breast cancer was observed for the codon 453 polymorphism [80]. One study examined both the codon 119 and codon 432 polymorphisms [81]. The two polymorphisms were genetically independent and no association with an increased breast cancer risk was found for any combination of them.

The CYP2D6 variant allele is the result of a deletion of a 17.5-kb region including the entire CYP2D6 gene [83]. In white populations, 5% are homozygous for this polymorphism [84,85]. These poor metabolizers are unable to metabolize agents such as debrisoquine and codeine [84]. Seven studies, with varying results, examined this polymorphism, three phenotypically [86 –88] and four genotypically [84,89–91]. When the phenotype studies were combined, a moderately increased breast cancer risk was found for poor metabolizers (OR: 2.22; 95% CI: 1.39–3.55). When the genotype studies were combined, an association was detected for carriers (homozygous and heterozygous combined) of the variant allele (OR: 1.49; 95% CI: 1.26–1.77). In conclusion, this polymorphism may play a role in increased breast cancer susceptibility.

Several polymorphisms have been described in the CYP19 gene. A tetranucleotide repeat polymorphism, (TTTA)n, is located in intron 4, approximately 80 nucleotides downstream from exon 4 [89,92]. A pooled analysis of five studies examining the (TTTA)10 allele polymorphism [93 –97] showed an OR of 1.59 (95% CI: 1.01–2.48).

The recent identification and characterization of the high-affinity metabolite of tamoxifen, 4-hydroxy-N-desmethyltamoxifen (endoxifen) [98], and the finding that endoxifen levels are reduced by the coadministration of SSRI [99], is an important observation that has potential therapeutic implications. It follows that as SSRIs block CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6), thereby inhibiting the metabolism of tamoxifen to endoxifen, then the efficacy of tamoxifen as an anticancer agent (treatment or chemopreventive) could be impaired by either the ubiquitous use of SSRIs to prevent hot flashes or the administration of tamoxifen to women with a defect in the CYP2D6 enzyme that no longer converts tamoxifen to endoxifen. Preliminary evidence suggests that this might be the case [100].

Prevention of ovarian cancer in BRCA1 carriers has also been discussed [101]. Testing for BRCA1 gene mutations has many implications, whether results are positive or negative. Those with positive results will be faced with decisions regarding the best management strategies. Negative results do not completely eliminate ovarian cancer risk. Current management options for carriers of the BRCA1 mutation include taking no action, increasing surveillance for ovarian cancer, and chemoprevention with oral contraceptives or prophylactic oophorectomy for those who have completed childbearing.

The diagnostic power of vaginal sonography and tumor marker measurement for prevention of ovarian cancer is still contradicted and under investigation.

Prevention of endometrium cancer includes avoidance of high-risk factors such as unopposed estrogen-replacement therapy and reducing high-risk factors such as obesity, hyperglycemia and hypertension.

Conclusion & future perspective

Preventive oncology will undoubtedly become a substantial part of the practicing oncologist's choice of drugs in the near future. Since the dramatic results of the Breast Cancer Prevention Trial [26], oncologists offer anti-estrogen therapies to women at high risk for breast cancer. Other chemopreventive strategies, such as NSAIDS in the primary or secondary prevention of cancers, are also likely to become common [102]. Genetic counseling has always been of importance, and as molecular genetics and testing advance oncologists are likely to recommend it, as well as increased surveillance and screening for second cancers to affected patients and their families. Preventive oncology should increasingly become a subject of interest, shifting the focus from surgery-, chemotherapy- and radiation-oriented therapists to prevention-oriented physicians [103,104].

Executive summary

Preventive oncology: recommendations

Obesity

– It has been demonstrated that women with BMI values in the highest quartile/quintile have an increase in breast cancer risk of approximately 20–40%. An increase in estrogen production is assumed to be the pathophysiological link between obesity and breast cancer risk.

– Furthermore, some evidence suggests that obesity increases the risk of endometrial cancer.

Exercise

– It has been estimated that 30–60 min of physical activity daily may reduce the risk of breast and endometrial cancer by 20–40%.

– In addition, physical activity after a breast cancer diagnosis may reduce the risk of death from the disease.

Dietary risk factors

– Moderate alcohol intake increases the risk of breast cancer and is a well-established risk factor for breast cancer.

– It is assumed that the reduced folate concentration that goes along with alcohol consumption mediates this increase in breast cancer risk.

– Greater red meat intake was found to correlate strongly with the risk of estrogen and progesterone receptor-positive breast cancer.

Chemoprevention

– Tamoxifen has been demonstrated to reduce the incidence of breast cancer by approximately 38%.

– Raloxifen is equivalent to tamoxifen but is favored by its side-effect profile.

Identification of risk factors for cancer prevention in postmenopausal women

The Gail model: a validated model of breast cancer risk assessment including risk factors, such as age, age at menarche, age at first live birth or nulliparity.

Breast density

– High breast density increases a woman's risk of breast cancer by a factor of four to six.

– The mechanism by which dense tissue increases the risk of breast cancer and whether or not a decrease in density lowers the risk are unknown.

Endogenous estrogen

– The risk of breast cancer was found to increase in a statistically significant manner with increasing serum concentrations of several sex hormones, including total, free and non–sex-hormone-binding globulin-bound estradiol.

– In patients with breast cancer, a 1 5% higher serum estradiol concentration was found.

SNP diagnosis

– Breast cancer has been shown to be associated with various polymorphisms, among them polymorphisms in the HRAS1, CYP1B1 and CYP2D6 genes.

– A total of 227,876 SNPs were estimated to correlate with 77% of known common SNPs in Europeans at r² over 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (p < 10⁻⁷). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1).

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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European Prospective Investigation into Cancer and Nutrition www.iarc.fr/epic/

Preventive Oncology in the Postmenopausal Woman

Abstract

Keywords

Preventive oncology: recommendations

Obesity

Exercise

Dietary risk factors

Chemoprevention

Identification of risk factors for cancer prevention in postmenopausal women

The Gail model

Breast density

Endogenous estrogen

C/1 Hormone replacement therapy

Single nucleotide polymorphisms

Conclusion & future perspective

Footnotes

References