The Breast 22 (2013) S30eS37 Contents lists available at SciVerse ScienceDirect The Breast journal homepage: www.elsevier.com/brst Nutrition and physical activity inﬂuence on breast cancer incidence and outcome Rowan T. Chlebowski* Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Building J-3, Torrance, CA 90502, USA a b s t r a c t Keywords: Breast cancer Nutrition Physical activity Dietary pattern Vitamins Introduction and aims: To provide a current perspective on nutrition and physical activity inﬂuence on breast cancer. Methods and results: A comprehensive literature review was conducted and selective presentation of ﬁndings follows. While some observational studies have associated higher dietary fat intake with higher breast cancer incidence, two full-scale randomized, clinical trials of dietary fat intake reduction programs were negative. However, a lifestyle intervention targeting fat intake reduction in the Women’s Intervention Nutrition Study (WINS), resulted in weight loss and also reduced breast cancer recurrences in women with early stage disease. Observational studies evaluating speciﬁc nutrient intakes and dietary supplements have provided mixed results. Several observational studies ﬁnd women with early stage breast cancer with lower 25-hydroxyvitamin D levels at higher recurrence risk, a ﬁnding requiring cautious interpretation. The lifestyle factor most strongly and consistently associated with both breast cancer incidence and breast cancer recurrence risk is physical activity. A meta-analyses of observational studies supports the concept that moderate recreational physical activity (about 3e4 h walking per week) may reduce breast cancer incidence and that women with early stage breast cancer who increased or maintain their physical activity may have lower recurrence risk as well. Feasibility of achieving increased physical activity and weight loss in women with early-stage breast cancer has been established. Two full-scale randomized clinical trials are evaluating weight loss/maintenance and increased physical activity in relation to recurrence risk in women with early-stage, resected breast cancer. Discussion/conclusions: Dietary intake may inﬂuence breast cancer but inﬂuence is difﬁcult to separate from inﬂuence of body weight. A consistent body of observational study evidence suggests higher physical activity has favorable inﬂuence on breast cancer incidence and outcome. While awaiting deﬁnitive evidence from ongoing randomized trials, breast cancer patients can reasonably be counseled to avoid weight gain and reduce body weight if overweight or obese and increase or maintain a moderate level of physical activity. Ó 2013 Published by Elsevier Ltd. Observational studies and emerging clinical trials are evaluating the role of dietary fat intake, dietary pattern, vitamin supplement use and physical activity on breast cancer incidence and breast cancer recurrence risk. Dietary fat intake The oldest identiﬁed association between lifestyle factors and breast cancer incidence has been the country-to-country differences in intake of dietary fat . Subsequent deﬁnitive evaluation of this relationship has been hindered by potential measurement error * Tel.: þ1 310 222 2219; fax: þ1 310 320 2564. E-mail address: [email protected] 0960-9776/$ e see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.breast.2013.07.006 associated with methodology unavailable to reliably estimate dietary fat intake by means such as food frequency questionnaires . For example, in a representative cohort report of 13,070 women, when a seven day food diary was used to determine intake, statistically signiﬁcant, positive association between higher fat intake and higher breast cancer risk was seen (RR 1.79, P-trend ¼ 0.05). However, when dietary fat intake was determined using a food frequency questionnaire, no signiﬁcant association with breast cancer was seen . To address the dietary fat and breast cancer hypothesis, the Women’s Health Initiative (WHI) dietary modiﬁcation (DM) trial randomized 48,835 otherwise healthy postmenopausal women with no prior breast cancer history to a dietary intervention (N ¼ 19,541) targeting dietary fat intake reduction and maintenance of nutritional adequacy or to a comparison group (N ¼ 29,002) receiving no dietary R.T. Chlebowski / The Breast 22 (2013) S30eS37 intervention. After 8.1 years follow-up, a statistically signiﬁcant reduction in dietary fat intake was achieved which was associated with modest weight loss. While there were fewer breast cancers in the intervention group, the difference was not statistically signiﬁcant (HR 0.91, 95% CI 0.83e1.01) . In an unplanned subgroup analyses, statistically signiﬁcant reductions in breast cancer incidence were seen in women with higher fat intake at entry (HR 0.78, 95% CI 0.68e0.95) and those adherent to the visit schedules. Post-intervention follow-up in the WHI DM trial continues. In a second primary prevention trial, women 30e65 years of age without a breast cancer history and with mammographic density greater than 50%, were randomized to a dietary intervention to reduce fat intake to 15% of total calories and increase carbohydrates or to a control condition. Percent calories from fat were 10% lower and there was a modest 1.6 kg lower body weight seen in intervention participants. However, there was no intervention inﬂuence on invasive breast cancer incidence after 10 years mean follow-up (HR 1.19, 95% CI 0.91e1.55) . The potential inﬂuence of a dietary intervention targeting fat intake on breast cancer recurrence has also been addressed in randomized clinical trials. The Women’s Intervention Nutrition Study (WINS) entered 2437 women with early-stage breast cancer who had received standard cancer management . The dietary intervention, designed to reduce fat intake while maintaining nutritional adequacy, was implemented with one-on-one visits with Registered Dietitians and resulted in a statistically signiﬁcant reduction in dietary fat intake from 29.2% to 20.3% calories from fat at one year (P < 0.0001) which was maintained through 60 months mean follow-up. While not an intervention target, a statistically signiﬁcant reduction in body weight of approximately 6 pounds was seen throughout. Relapse-free survival was the primary study endpoint and was favorably impacted by the dietary intervention (HR 0.76, 95% CI 0.60e0.98, P ¼ 0.03 from the adjusted Cox proportional hazards model) . Due to funding issues, detailed follow up for longer S31 intervals was not possible. However, a survival analysis was completed at 108 months follow-up based on death registry information. Overall, there were fewer deaths in the intervention group (HR 0.82, 95% CI 0.64e1.07) but the difference was not statistically signiﬁcant (P ¼ 0.146). However, in a subgroup analysis, survival was signiﬁcantly greater in women with ER negative, PR negative breast cancers (HR 0.36, 95% CI 0.18e0.74, P ¼ 0.003) . A second study, the Women’s Healthy Eating and Living (WHEL) examined a different dietary intervention in early-stage breast cancer patients . Randomized were 3080 pre-and postmenopausal patients, to dietary intervention targeting increased vegetable servings, 16 ounces daily vegetable juice, increased fruit and ﬁber intake, and a target of reducing fat intake to 15% to 20% calories from fat. Substantial increase in fruit and vegetable intake was achieved, however no sustained decrease in percent energy from fat was seen and, at year 6, intake of dietary fat was nearly identical to the baseline intake, and no weight change occurred. There was no effect of the dietary intervention on breast cancer incidence . The full scale adjuvant lifestyle trials, completed and ongoing are, outlined in Table 1. While there are differences between the WINS and the WHEL trial study populations and interventions, the hypothesis that emerged from the WINS trial, namely that a lifestyle intervention targeting dietary fat intake reduction which is associated with moderate weight loss will reduce breast cancer recurrence, was not tested in the WHEL trial as neither sustained dietary fat intake reduction nor weight loss were seen . Ongoing studies, to be discussed later, are more directly addressing the WINS hypothesis. Vegetables and fruits The ﬁndings regarding vegetable and fruit intake, assessed either separately or combined, on breast cancer incidence and outcome have been mixed [10e12]. Some variability may relate to Table 1 Randomized Clinical Trials evaluating lifestyle change in early stage, resected breast cancer: study designs and reported outcome. Eligibility Stage Time from surgery Chemotherapy Hormonal therapy Receptor status Age Weight/BMI kg/m2 Diet at baseline Intervention Number of pts (randomization type) Intervention target Diet Body weight Physical activity Endpoint Primary breast cancer outcome result a WINS (21) WHEL (22) SUCCESS e C (91) DIANA-5 IeIII A 12 months AC, CMF, FAC, or AC / Paclitaxel Tamoxifen Any 48e79 yrs Any 20% caloric from fat Individual registered dietitian face-to-face visits IeIII A 48 months Any (before randomization) High riska <5 y Any 2437 (3:2 randomization) 3088 (1:1 randomization) Node þ, high risk node At diagnosis Randomized to 3 FEC / 3D vs 6 DC Protocol deﬁned HER2 negative Pre and postmenopausal BMI 24e40 Any Telephone calls from personal lifestyle coach assisted by tracking team (nurses, dieticians, physicians and psychologists) 1000 (estimate) (1:1 randomization) Y to 15% cal from fat; Vegetable: increase; Fruit: increase Y to <20% cal from fat; Vegetables: increase to 5 serving/d and 16 oz vegetable juice/d; Fruit: increase to 3 servings/d N/A N/A Y to 20e25% cal from fat; Vegetable: increase (no target); Fruit; increase (no target) Mediterranean-macrobiotic diet Loss target Increase to 150e200 min moderate PA/wk Breast cancer recurrence Pending Loss target Increase to 210 min moderate PA/wk Breast cancer events Pending N/A N/A Relapse-free survival HR 0.76 (95% CI 0.60e0.98, p ¼ 0.034) Any Any 18e70 yrs Any Any Telephone calls and cooking classes Breast cancer event free-survival 0.96 (95% CI 0.80e1.14, p ¼ 0.63) ER negative or metabolic syndrome on high testosterone or insulin. Any 35e70 Cooking classes, conferences, exercise sessions 1214 (1:1 randomization) S32 R.T. Chlebowski / The Breast 22 (2013) S30eS37 differences in absorption and metabolism between individuals as, for example, blood concentrations of carotenoids are more strongly associated with lower breast cancer risk than are carotenoids intake assessed by questionnaire . The available evidence has been recently summarized in a comprehensive metaanalysis of 20 cohort studies with 993,466 women followed 11e20 years. Those analyses associated higher vegetable intake with lower estrogen receptor negative breast cancers (RR 0.8; 95% CI 0.74e0.90) but there was no association with estrogen receptor positive cancers (RR 1.04; 95% CI 0.97e1.11) . Additionally, no associations with fruit intake and breast cancer incidence were identiﬁed (Table 2). Regarding vegetables/fruit intake inﬂuence on breast cancer recurrence, the negative randomized WHEL study, where substantial increase in both fruits and vegetables failed to inﬂuence breast cancer recurrence risk, has been discussed previously . Dietary patterns A number of studies have evaluated the inﬂuence of various dietary patterns on breast cancer incidence and recurrence risk. The diets are often characterized as Western/unhealthy (those with high red and or processed meat, potatoes, sweets, high-fat dairy) or prudent/healthy dietary patterns, those with high fruits and vegetable intake and include poultry, ﬁsh, low-fat dairy and whole grains. The latter pattern is characterized as Mediterranean if it includes olive oil emphasis. A number of standardized measures have been developed to provide various dietary quality scores. Examples include the Alternate Healthy Eating Index (AHEI), Diet Quality Index-revised (DQI), Recommended Food Score (RFS), and adapted Mediterranean Diet Score (arMDS) . In a recent metaanalysis and systematic review, 18 case-control and 17 cohort studies were identiﬁed where prudent/healthy and Western/unhealthy diets were evaluated regarding inﬂuence on breast cancer risk. Breast cancer risk was lower in those with high compared to low prudent/healthy dietary patterns (OR 0.89, 95%CI 0.81e0.99, P ¼ 0.02) but there was no difference in breast cancer risk between those with high compared to low Western/unhealthy dietary patterns (OR 1.09, 95% CI 0.98e1.22, P ¼ 0.12) (Table 2) . Associations of a Mediterranean diet and breast cancer have been evaluated in several reports [17e19]. In the large European Prospective Investigation into Cancer and Nutrition (EPIC) cohort of 335,062 women from 10 European countries, the arMDS was used to examine associations with breast cancer incidence. Overall, women with high adapted Mediterranean diet score had lower breast cancer risk (HR 0.94, 95% CI 0.88e1.00, P ¼ 0.048) with stronger ﬁndings related to ER, PR negative cancers . In a casecontrol study in Cyprus, higher consumption of vegetables and ﬁsh and olive oil was associated with lower breast cancer risk . However, ﬁndings with the Mediterranean diet are mixed and other studies ﬁnd no association [17,20]. The inﬂuence of Mediterranean diets on postmenopausal breast cancer survival has been evaluated in 2729 women with early stage breast cancer in the Nurse’s Health Study where diet was assessed one year after cancer diagnosis. In subgroup analyses, women with low physical activity (<9 Met/h/wk) and high adapted Mediterranean score had lower non-breast cancer related death (RR 0.39, 95% CI 0.22e0.75, P ¼ 0.004) . While further study is required, current ﬁndings suggest that a Mediterranean dietary pattern perhaps has only a modest association with breast cancer outcomes but has greater potential for beneﬁt on other health events. In summary, studies examining dietary intakes and dietary patterns ﬁnd only modest associations with breast cancer incidence and inconsistent results. A remaining question is whether any speciﬁc dietary intake or pattern has an inﬂuence on breast cancer outcomes if body weight is optimal and moderate physical activity is maintained. Available evidence does not permit separation of these potential inﬂuences. Vitamins and supplements The ﬁndings regarding multivitamin and supplement use on breast cancer incidence and outcome are mixed. With respect to breast cancer incidence, in a cohort of 161,808 postmenopausal women followed in the Women’s Health Initiative, persistent multivitamin use, compared to nonuse, had no inﬂuence on invasive breast cancer incidence (HR 1.00, 95% CI 0.92e1.09) . In terms of inﬂuence on breast cancer recurrence, in a populationbased, prospective cohort of 4877 Chinese women, aged 20e75 years with invasive breast cancer, those who used anti-oxidants (vitamin E, vitamin C, multivitamins) had 18% lower mortality risk (HR 0.82, 95% CI 0.65e1.02) and 22% lower breast cancer recurrence risk (HR 0.78, 95% CI 0.63e0.95) compared to nonusers . In contrast, in a much smaller study, non-signiﬁcantly higher breast cancer mortality (HR 1.75, 95% CI 0.83e2.69) and lower disease-free survival (HR 1.55, 95% CI 0.94e2.54) was seen in women following a mega dose vitamin supplement regimen . These results, and related ﬁndings, have raised concerns that Table 2 Selected recent meta-analysis of diet any pattern, physical activity and Breast Cancer incidence and outcome. Lead author Study group Component evaluated Endpoint Endpoint Brennan Brennan Jung 10 cohorts 10 cohorts 20 cohorts 993,466 women Prudent/healthy dietary pattern (high vs low) Western/unhealthy dietary pattern (high vs low) Fruit/vegetable intake (high vs low) OR 0.93 (0.88e0.98) OR 0.99 (0.90e0.98) Vegetables For ER () 0.82 (0.74e0.90) For ER (þ) 1.04 (0.97e1.11) Breast cancer incidence Breast cancer incidence Breast cancer incidence Wu 31 cohorts 63,786 women Physical activity (high vs low) Obraheim 4 cohorts 10,372 women Physical activity after cancer diagnosis Fruits For ER () 0.94 (0.85e1.04) For ER (þ) BLANK (BLANK) Vegetables Postmenopausal RR 0.87(0.84e0.92) Premenopausal RR 0.77 (0.72e0.84) For ER, PR RR 0.50 (0.73e0.87) For ERþ, PRþ RR 0.92 (0.87e0.98) Activity Level (MET h/wk) 2.8e8.9 HR 0.76 (0.61e0.95) >8.0 HR 0.54 (0.40e0.73) >15.0 HR 0.61 (0.46e0.81) Breast cancer incidence Breast cancer mortality R.T. Chlebowski / The Breast 22 (2013) S30eS37 antioxidants and multi-vitamins may interact negatively with radiation therapy and chemotherapy regimens [24,25]. There are methodological issues involved in comparing clinical outcomes in pills/supplement users to non-pill users. In the Women’s Health Initiative hormone therapy trials, the inﬂuence of placebo adherence on various clinical outcomes was evaluated. Women who were placebo adherent (that is, were taking 80% or more of assigned study pills) compared to those less adherent to placebo assignment had signiﬁcantly lower risk of invasive breast cancer (HR 0.73, 95% CI 0.53e1.00), myocardial infarction (HR 0.59, CI 0.50e0.95) and death (HR 0.64, 95% CI 0.51e0.82) in analyses adjusted for multiple variables associated with these outcomes . Such ﬁndings suggest studies comparing pill users to nonusers must be interpreted with caution. Vitamin D One supplement which has received considerable attention with respect to breast cancer is vitamin D. Selected observational studies associate higher vitamin D intake and higher 25-hydrox vitamin D levels with higher breast cancer risk [27,28]. As a result, some recommend monitoring 25-hydroxyvitamin D levels and providing vitamin D supplementation to reduce breast cancer risk . With respect to associations with breast cancer and vitamin D, the ﬁndings are mixed. In meta-analyses, in most caseecontrol studies, where 25-hydroxyvitamin D is measured following breast cancer diagnosis, strong associations between lower 25-hydroxyvitamin D levels and higher breast cancer risk are seen. However, in the more reliable cohort studies, where 25-hydroxyvitamin D levels are measured before breast cancer diagnosis, such associations are rarely seen . In addition, both low body weight and high physical activity are associated with both low breast cancer risk and high 25-hydroxyvitamin D levels representing potential for confounding in analyses not adjusted for these variables [28,31]. The Women’s Health Initiative conducted a randomized clinical trial involving 36,202 postmenopausal women who received either supplementation with 1000 mg elemental calcium as calcium carbonate and 400 IU vitamin D3 or placebo. After seven years of follow-up, breast cancer incidence was similar in the two randomization groups (HR 0.96, 95% CI 0.85e1.09) . In a nestedcase-control study within this randomized trial, there was no association seen between the 898 women with breast cancer and 895 matched cancer-free controls with respect to 25-hydroxyvitamin D levels in analyses adjusted for body weight and physical activity. In analyses attempting to explain differences between individual 25hydroxyvitamin D levels, about 80% of the difference remained unexplained even after consideration of vitamin D intake from both diet and supplements as well as inﬂuence of body mass index and physical activity differences [31,32]. Thus, a large component of 25hydroxyvitamin D level differences between individuals likely are genetically determined making causal attribution of breast cancer to differences in 25-hydroxyvitamin D levels problematic. S33 There is an interesting signal which requires further attention regarding 25-hydroxyvitamin D levels and breast cancer recurrence. In an initial observation, Goodwin and colleagues  found that women with early-stage breast cancer were more likely to have recurrence if they have low 25-hydroxyvitamin D levels. Subsequently, there have been six additional reports of this relationship and they provide mixed ﬁndings (Table 3). Four reports support a signiﬁcant association between low 25-hydroxyvitamin D levels and higher recurrence risk [34e37] and two do not [38e40]. With mixed ﬁndings the question remains open. A study to determine whether a randomized intervention trial of vitamin D as adjuvant therapy in patients with breast cancer was feasible found that, in metropolitan populations in Canada and the US, 84% of breast cancer patients were already taking vitamin D at an average dose of 1000 mg/d, suggesting a trial of this issue is not feasible, at least in populations receiving contemporary Western medical intervention . Physical activity Perhaps the lifestyle factor most strongly and consistently associated with both breast cancer incidence and breast cancer recurrence is physical activity . In observational studies, a recent meta-analysis of 76 studies found higher levels of physical activity associated with lower breast cancer incidence (RR 0.80, 95% CI 0.78e0.84) with similar ﬁndings for pre and postmenopausal women and no differences for relatively low and high intensity physical activity level . In a meta-analysis of 31 prospective studies were reported similar ﬁndings with higher physical activity level associated with lower breast cancer incidence in both pre-and postmenopausal women . While many studies have associated moderate physical activity with lower breast cancer recurrence risk [44e49], of greatest clinical relevance are studies which compared the timing of the physical activity in relation to the cancer diagnosis (Table 2). Such studies address the clinically relevant question of whether a women who is physically active after diagnosis reduces her risk of disease recurrence. In the Nurse’s Health Study, 2987 breast cancer patients with stage 1e3 disease provided self-report of physical activity prior to diagnosis (done retrospectively) and at about two years after diagnosis. In multi-variant adjusted analyses, physical activity over 9 MET/h/wk was associated with lower recurrence risk . In a study by Irwin and colleagues , information on physical activity was prospectively collected both before and after breast cancer diagnosis in a total of 2076 early-stage patients. In multi-variant analyses, breast cancer deaths were lower only women who maintained an active physical activity pattern or who increased physical activity post diagnosis but not in those who were inactive in both or those who were previously active but decreased their activity post diagnosis. A meta-analysis of such studies found post-diagnosis physical activity was associated with 34% fewer breast cancer deaths (P < 0.001) and 41% fewer deaths from all causes (P < 0.001) . Table 3 Cohort studies of 25-hydroxyvitamin D concentration and subsequent Breast Cancer outcome. Lead author n Breast cancer category Country Follow-up (mean) Study outcome Goodwin  Piura , Pritchard  Jacobs  Vrieling  Tretli  Coleman  Kim  512 667 1024 1294 251 872 310 Early stage, Early stage, Early stage, Stage IeIV Stage IeIV Early stage, Early stage, Canada Canada USA Germany Norway International Korea 11.6 yrs 7.9 yrs 7.3 yrs 5.8 yrs (median) N/A 4.4 yrs 1.9 yrs Signiﬁcant association No signiﬁcant association No signiﬁcant association Signiﬁcant association Signiﬁcant association Signiﬁcant association Signiﬁcant association (luminal cancers) Brennan et al. AM J Clin Nutr 2010;91:1294e302. resected resected resected resected resected S34 R.T. Chlebowski / The Breast 22 (2013) S30eS37 A number of intervention strategies have been proposed to increased physical activity. One interesting observation relates to the association between dog ownership and physical activity. In two comparable cross-sectional surveys of adults, dog owners compared to non-dog owners were signiﬁcantly more likely to meet the recommended physical activity and walking levels in analyses adjusted for social-demographic, neighborhood, social environment and interpersonal factors [51,52]. Potential mechanisms of action mediating lifestyle inﬂuence on breast cancer A biological model relating potential inﬂuence on biomarkers of exercise with implications for postmenopausal breast cancer risk is outlined in Fig. 1 . The model also could be reasonably applied to weight loss and perhaps some dietary pattern differences as well. As seen, insulin, estrogen, IGF-1, and markers of inﬂammation are potential targets mediating the inﬂuence of physical activity on breast cancer incidence and outcome . A series of cohort analyses and small randomized trials have evaluated the effects of lifestyle interventions on such potential mediating factors with representative results outlined below. In healthy postmenopausal women (in DIANA-1) [55,56] and in breast cancer patients (DIANA2) , in randomized trials, where the intervention dietary component was a diet based on traditional Mediterranean and macrobiotic recipes, intervention group participants had signiﬁcantly decreased body weight, serum testosterone (18%), and bioavailable estrogen and IGF-1 [55,56]. McTiernan and colleagues evaluated the inﬂuence of 12 months of increased physical activity compared to control stretching intervention in a randomized trial in healthy postmenopausal women and found that moderate intensity recreational activity signiﬁcantly reduced serum insulin and testosterone, with some inﬂuence on estrogen levels seen [58,59]. In the Yale Exercise and Survivorship Study, a program to increase physical activity lowered IGF-1 levels . In the WHI cohort, lower insulin levels in 2307 participants were found in women with lower total caloric intake and higher physical activity . These studies provide rationale for moving forward with deﬁnitive randomized trials evaluating lifestyle interventions targeting body weight and physical activity. Lifestyle feasibility randomized trials in early-stage breast cancer Several randomized trials have evaluated the feasibility of conducting lifestyle interventions in full-scale adjuvant breast cancer trials. The WINS UK (United Kingdom)  trial was designed to evaluate the feasibility of achieving substantial dietary fat intake reduction in an adjuvant breast cancer setting similar to that in the WINS US report . While fat intake reduction was achieved, a fullscale adjuvant trial did not receive funding support. A similar pilot study randomized early stage breast cancer patients to a 6 month exercise and hypo caloric diet regimen or control. Reductions in fat intake and waist circumference were seen . In the Reach out to Enhance Wellness (RENEW) study, the efﬁcacy of a telephone-based lifestyle intervention in effecting changes in diet, physical activity and weight was demonstrated in 641 patients with early-stage colon, prostate, and breast cancer . Similarly, the Nutrition and Exercise for Women (NEW) trial evaluated the inﬂuence of lifestyle interventions on biomarkers associated with breast cancer outcomes . The Lifestyle Intervention Study for Adjuvant Treatment of Early Breast Cancer (LISA) trial is a randomized controlled trial examining the feasibility of delivering a lifestyle intervention targeting dietary fat intake reduction, weight loss, or weight maintenance if weight appropriate, and increase in physical activity using a centrally mediated intervention. This multicenter clinical trial, involving 328 early-stage breast cancer patients, conducted in Canada and the US was successful in achieving weight loss and increased physical activity  and an expanded feasibility study is under development. Another ongoing multi-center, randomized vanguard trial in earlystage breast cancer patients is the Exercise and Nutrition to Fig. 1. Biological model relating proposed biomarkers to long term exercise and postmenopausal breast cancer risk. R.T. Chlebowski / The Breast 22 (2013) S30eS37 Enhance Recovery and Good health for You (ENERGY) trial. This study will enter 693 overweight/obese breast cancer patients with an intervention goal of weight loss . Lifestyle ongoing randomized trials in early-stage breast cancer Two randomized clinical trials are evaluating lifestyle interventions in relatively large trials. The SUCCESS-C is a Europeanbased intervention trial targeting increased physical activity and weight loss/maintenance implemented in a randomized fashion against the background of a breast cancer adjuvant trial evaluating several taxane regimens. Approximately 1000 patients will be in this ongoing trial . The DIANA-5 trial is also an ongoing randomized trial evaluating lifestyle inﬂuence on breast cancer recurrence. The intervention is a diet based on Mediterranean and macrobiotic recipes and principles together with moderate physical activity increase. The study has randomly assigned 1208 patients between 2008 and 2010 to be followed through 2015 . The study design and available results from the two completed adjuvant lifestyle trials and the 2 ongoing trials are outlined in Table 1. Completion of these studies will allow more deﬁnitive assessment of the hypothesis that lifestyle interventions targeting weight and increased physical activity can inﬂuence breast cancer recurrence. Summary Given available information, it is unclear whether any speciﬁc dietary component or pattern can inﬂuence breast cancer outcome if weight is optimal and moderate physical activity maintained. However, the evidence for a potentially important role for weight loss/maintenance (reviewed elsewhere) and moderate intensity physical activity in impacting breast cancer outcome is strong and compelling. Perhaps results from ongoing and planned randomized trials will lead to greater incorporation of lifestyle interventions in routine clinical practice. In the era of increasing complexity and attention to development of targeted interventions for breast cancer therapy, the lifestyle interventions reviewed in this document have demonstrated S35 inﬂuence on mediators of several pathways strongly associated with breast cancer incidence and recurrence including insulin, estrogen, IGF-1, and inﬂammatory mediators. In this regard, lifestyle change can be felt to represent a multi-targeted therapy. More importantly, the lifestyle changes have been successfully implemented in multi-center clinical trials at relatively low cost using central, telephone-based intervention strategies with minimal side effects as the behaviors return women to their evolutionary norms. In terms of balance regarding research allocation and implementation in clinical practice, perhaps history regarding tobacco and lung cancer risk provide an informative lesson. For nearly a half century concerted research attention was extended in the pursuit of the exact mechanism mediating the effect of tobacco use on lung cancer risk. At some point a decision was made to emphasize stopping tobacco use and programs to implement smoking cessation were evaluated and introduced in public health practice with great inﬂuence on the target disease . Perhaps lifestyle intervention and breast cancer could be considered in the same light. There is now strong evidence regarding the relation between lifestyle factors and breast cancer risk when we examine the substantial increase in breast cancer risk in Asian countries including Japan, China and Korea from 1975 to the present where breast cancer mortality has increased by over 100% in association with adaptation of Western lifestyles (Fig. 2) . During the same period in the USA, the introduction of screening mammography and adjuvant breast cancer therapy has been associated with a comparatively modest 28% decrease in breast cancer mortality . While the individual components responsible for the increase in breast cancer mortality in Asia cannot be deﬁnitively evaluated, it is highly likely that change in diet, obesity, and physical activity play a major role. It may be time to re-examine the relative importance afforded lifestyle inﬂuence on breast cancer incidence and outcome relative to other research approaches. While waiting deﬁnitive evidence from ongoing randomized trials how should the current weight of evidence impact clinical practice? Given available information, breast cancer patients can reasonably be counseled to avoid weight gain and reduce body weight if overweight or obese and, perhaps most importantly, to increase or maintain a moderate level of physical activity. Fig. 2. Age-adjusted Breast Cancer Mortality in Korea and Japan (1960e2010). S36 R.T. Chlebowski / The Breast 22 (2013) S30eS37 Conﬂict of interest statement None declared. Acknowledgments Funding/support: Studies from the Women’s Health Initiative (WHI) program reported here were funded by the National Heart, Lung, and Blood Institute with additional support from the National Cancer Institute. Disclosure: Dr. Chlebowski has received consulting fees from AstraZeneca, Novartis and Pﬁzer and lecture fees from Novartis. References  Carroll KK, Gammal EB, Plunkett ER. Dietary fat and mammary cancer. 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Impact of the Lifestyle Intervention Study in Adjuvant Treatment of Early Breast Cancer (LISA) weight loss intervention upon physical activity. Cancer Res April 26, 2011;70:S2e6. Rock CL, Byers TE, Colditz GA, Demark-Wahnefried W, Ganz PA, Wolin KY, et al. Reducing breast cancer recurrence with weight loss, a vanguard trial: the Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial. Contemp Clin Trials 2012;34(2):282e95. Rack B, Andergassen U, Neugebauer J, Salmen J, Hepp P, Sommer H, et al. The German SUCCESS C Study-The ﬁrst European lifestyle study on breast cancer. Breast Care 2010;5:395e400. Villarini A, Pasanisi P, Traina A, Mano MP, Bonanni B, Panico S, et al. Lifestyle and breast cancer recurrences: the DIANA-5 trial. Tumor 2012;98:1e18. Hymowitz N. Smoking and cancer: a review of public health and clinical implications. J Natl Med Assoc 2011;103:695e700. Shin HR, Boniol M, Joubert C, Hery C, Haukka J, Autier P, et al. Asian populations: Hong Kong, Japan, Korea, Singapore and Taiwan. Cancer Sci 2010;101:1241e6. Zhang J, Dhakal IB, Zhao Z, Li L. Trends in mortality from cancers of the breast, colon, prostrate, esophagus, and stomach in East Asia: role of nutrition transition. Eur J Cancer Prev 2012;21:480e9. The Breast 22 (2013) S38eS43 Contents lists available at SciVerse ScienceDirect The Breast journal homepage: www.elsevier.com/brst Sex hormones and breast cancer risk and prognosis Elizabeth Folkerd*, Mitch Dowsett The Academic Department of Biochemistry, The Royal Marsden NHS Foundation Trust, Wallace Wing, Fulham Road, London SW3 6JJ, UK a b s t r a c t Keywords: Breast cancer Risk Prognosis Sex hormones The study of large prospective collections of plasma samples from women prior to the development of breast cancer has ﬁrmly established certain sex steroids as being signiﬁcantly associated with risk. The strongest associations have been found in postmenopausal women in whom the within person variability of most hormones is markedly reduced but some positive associations have also been seen in premenopausal women. Plasma estrogens show the strongest correlations with risk and these are strengthened by measurement or calculation of the proportion of estradiol that circulates free of sex hormone binding globulin (SHBG), consistent with this being the most active fraction. The relationships have been reported to potentially explain virtually all of the association of breast cancer with body mass index in postmenopausal women; this is likely to be due to non-ovarian estrogen synthesis being prominent in subcutaneous fat. These strong relationships have led to plasma and urine estrogen levels being used as intermediate end-points in the search for genes that affect breast cancer risk via their role in steroid disposition. Plasma androgen levels also show a relationship with breast cancer risk that is weakened but not eliminated by ‘correction’ for estrogen levels. This has been argued to be evidence of the local production of estrogens being important in the etiology of breast cancer. Given that plasma steroid levels do not correlate closely with mammographic density, which is strongly associated with risk, the opportunity exists to combine the two factors in assessing breast cancer risk but the low availability of suitable estrogen assays is a major impediment to this. In established breast cancer, plasma estrogens have been found to correlate with gene expression of estrogen dependent genes and the expression of these varies across the menstrual cycle of premenopausal women. There is infrequently a need for routine measurement of plasma estrogen levels but it has been important in the comparative pharmacology and dose-related effectiveness of aromatase inhibitors. Measurement may be needed to identify residual ovarian function in women who have amenorrhea subsequent to cytotoxic chemotherapy indicating their unsuitability for aromatase inhibitor treatment. Use of highly sensitive assays has also revealed that the association between BMI and plasma estrogen levels persists in patients on 3rd generation aromatase inhibitors and that measurable increments in plasma estrogen levels occur with some vaginal estrogen preparations that are of concern in relation to treatment efﬁcacy. Ó 2013 Elsevier Ltd. All rights reserved. Introduction The observation by Sir George Beatson  over a century ago that in premenopausal women some breast cancers regressed in response to oophorectomy was the ﬁrst of many observations that link reproductive physiology to the risk of developing breast cancer and to the treatment and prevention of this disease. Evidence that associates sustained exposure to higher levels of estrogens with the development of breast cancer, have led to the successful application * Corresponding author. Tel.: þ44 (0)2078082885; fax: þ44 (0)2073763918. E-mail address: [email protected] (E. Folkerd). 0960-9776/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2013.07.007 of endocrine agents in chemoprevention trials and the development of strategies for the prevention of breast cancer using such agents [2e4]. A strong dependence of many breast cancers on estrogen for their growth underpin the successful use of endocrine agents in the adjuvant setting, contributing to a marked improvement in prognosis. This review will consider factors that inﬂuence circulating sex steroids, with an emphasis on estradiol levels, in both pre and postmenopausal women, together with the consequences of the hormonal milieu on the development, treatment and prognosis of breast cancer. Some of the scientiﬁc impact of research in this sphere is limited by the technical limitations of the methodology used to quantitate steroids, particularly estradiol, and consideration E. Folkerd, M. Dowsett / The Breast 22 (2013) S38eS43 will be given to the utility of estrogen measurements and the problems associated with technological difﬁculties. Sex steroid levels in pre and postmenopausal women In premenopausal women estrogen is produced in the granulosa cells of the ovary. The aromatase enzyme converts testosterone and androstenedione, to estradiol and estrone respectively. This ovarian production of estradiol is regulated by feedback control on the levels of follicle stimulating hormone. The secretion of estradiol is cyclical in premenopausal women, with large ﬂuctuations in the concentration of circulating estradiol and progesterone throughout the menstrual cycle as oocytes mature and are released. Aromatase is also expressed, albeit at lower levels, in peripheral tissues such as adipose tissue and skin, where activity is under control of other factors including c-AMP, prostaglandin E2 and glucocorticoids . After the menopause when estrogen and progesterone output from the ovary declines, production of circulating estradiol continues in the peripheral tissues. Levels of circulating estradiol are not subject to large ﬂuctuations in postmenopausal women, remaining fairly constant within an individual  and low (10e60 pmol/l) in comparison to those found in younger women (70e1500 pmol/l). The adrenal production of androgens continues after the menopause but output declines with age . Despite the plethora of breast cancer research over the years using circulating estradiol measurements as an end point, some researchers have questioned the value of such measurements in postmenopausal women and argued that circulating estrogens are only a modest reﬂection of tissue metabolism and that tissue levels should be measured to reﬂect exposure. Estrogen levels in tissues such as the breast are higher than circulating levels in postmenopausal women. However recent reviews [8,9] have concluded that in benign breast tissue plasma estrogens are a good surrogate for tissue levels because of the rapid exchange between the tissue and the extracellular matrix. Breast tumors have higher levels of estrogen than surrounding tissues  and this is thought to be largely a consequence of an enhanced uptake from the circulation rather than an increase in aromatization within the tumor tissue . Circulating levels of estradiol reﬂect overall production and the success of systemic aromatase inhibition in the treatment of breast cancer underlines the validity and utility of steroid measurements as a tool in epidemiology and breast cancer care. Circulating steroid levels and the risk of breast cancer Sex steroids stimulate the growth and division of breast cells and the observation that endogenous levels of sex steroids are associated with breast cancer risk and sustained tumor growth in postmenopausal women is well established . Remarkably Zhang et al. have reported that one measurement of endogenous hormone levels in a postmenopausal woman can predict risk of hormone responsive breast cancer for up to 16e20 years . The major problems associated with getting precise estimates of relative risks of breast cancer are the need for large sample sizes and the heterogeneity between laboratories in the estimation of the hormones. The Endogenous Hormones and Breast Cancer Collaborative Group conducted an overview of nine prospective studies of risk  and for estradiol found an overall increase in relative risk of 1.29 (95% conﬁdence interval, 1.15e1.44; p < 0.001) for every doubling of estradiol concentration. They found considerable between laboratory variations particularly for estradiol measurements and therefore had to carry out the analysis of risk by allocating each measured hormone concentration into ﬁve groups with cut-off points deﬁned by study-speciﬁc quintiles i.e. they looked at the distribution of the hormone concentrations not the S39 measured values. This approach allowed the group to make valuable epidemiological observations but probably limited their ability to determine the strength of the relationships accurately. For most androgens and estrogens there is an approximate doubling of the risk of breast cancer between women in the lowest quintile of circulating levels of sex hormones and those in the highest quintile. Conversely, increasing levels of SHBG are associated with a decrease in breast cancer risk. More than 97% of the most potent sex steroids, estradiol and testosterone, in blood, is circulated bound to albumin and SHBG. Only the small unbound fraction is able to enter the cell and bind to steroid receptors and therefore this free fraction is often considered to be most active and most closely allied to breast cancer risk. The concentration of SHBG is intrinsically related to the bioavailability of sex steroids and hence risk of developing disease. In premenopausal women, the cyclical secretion of hormones complicates comparative interpretation of circulating hormone levels between women. However this problem can be overcome by collecting samples at deﬁned phases of the menstrual cycle. In a large caseecontrol study nested within the Nurses’ Health Study II, where they collected samples in the early follicular and mid-luteal phases, women with the highest quartiles of follicular total and free estradiol levels had a higher risk of breast cancer (RR ¼ 2.1[95% CI ¼ 1.1e4.1] and RR ¼ 2.4 [95%CI ¼ 1.3e4.5], respectively . Other studies, where the collection of samples has been across the whole menstrual cycle, have not reported any associations of estradiol and breast cancer risk although the European Prospective Investigation into Cancer and Nutrition (EPIC) did ﬁnd a modest association between high levels of androgens and risk, and a reduction in risk with increasing progesterone concentrations . Other than body weight, the determinants of the levels of circulating steroids are not known, although in a recent review the modest effects of alcohol, exercise, diet and smoking were described . The highly variable rates of breast cancer incidence worldwide suggest that ethnic groups may exhibit genetic heterogeneity with respect to steroid disposition and disease susceptibility. There is evidence that plasma levels of sex steroids are heritable . Studies of monozygotic and dizygotic twins have examined the familial associations of circulating hormone levels and found both heritability and shared environmental factors inﬂuence the associations demonstrated between the endogenous sex steroids levels found in siblings [18e20]. It has been possible to increase the power of genome-wide association studies to detect variants with modest effects, by targeting genes that might inﬂuence hormone synthesis and regulation and hence risk of disease. Using steroid concentrations as intermediate end-points for breast cancer risk it has been possible to identify highly statistically signiﬁcant associations between common genetic variants of both the CYP19 (aromatase) and SHBG genes and circulating sex hormone levels [21e23]. Dunning et al.  reported that CYP19 SNPs (rs10046 and [TCT]þ/) were associated with differences in plasma estradiol levels in postmenopausal women. They also found SHBG SNPs (50 un-translated region [50 UTR] g-a and D356N) were associated with SHBG levels. The SNPs explained 2.4% and 0.6% of the variance in SHBG levels respectively but in a supplementary caseecontrol study none of the SNPs were associated with breast cancer risk. In premenopausal women Johnson et al.  using a protocol that was developed to allow for the cyclical secretion of hormones, found a tag SNP (rs10273424) mapping 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in estrone glucuronide levels in urine. The SNP was associated with a moderate reduction in the risk of breast cancer in patients who were under ﬁfty at diagnosis (OR ¼ 0.91, 95% CI ¼ 0.83e0.99; P ¼ 0.03). The results may have wider implications for breast cancer patients with the SNP since S40 E. Folkerd, M. Dowsett / The Breast 22 (2013) S38eS43 CYP3A4, which is the most frequently expressed CYP3A gene, has a role in the metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer . The magnitude of the effect on hormone levels for a particular polymorphism is quite modest. Consequently, very large casee control studies would be necessary to quantify the risk associated with a particular SNP accurately. Higher levels of risk may be conferred according to the combined accumulation of polymorphisms in low penetrance genes associated with hormone metabolism in a particular individual. Effect of BMI In postmenopausal women increasing body mass index (BMI) is associated with a concomitant rise in the risk of breast cancer . It has been estimated that for every 1 kg/m2 increase in BMI there is a 3% increase in the risk of breast cancer . In obesity the amount of adipose tissue available for estrogen production increases while the amount of SHBG goes down thus increasing the bioavailable free fraction of circulating estradiol. A meta-analysis by the Endogenous Hormones and Breast Cancer Collaborative Group looking at whether sex hormone levels explain the relationship between BMI and breast cancer risk in postmenopausal women, demonstrated that adjusting for free estradiol reduced the excess risk for breast cancer associated with a 5 kg/m2 increase in BMI, from 19% to 2% . There was a moderate effect after adjusting for SHBG, but adjusting for androgens had a negligible impact. Androgens have been shown to be associated with breast cancer risk to the same degree as estrogens  but in contrast, the impact of high levels of endogenous androgens on the etiology of breast cancer appears to be unrelated to BMI  The inﬂuence of estrogens and BMI on breast cancer extends beyond the risk of developing disease to treatment efﬁcacy, progression and outcome [27e30]. In the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trial  postmenopausal women with hormone responsive breast cancer who had a BMI > 35 kg/m2 before treatment had a higher risk of recurrence and death than those with a low BMI (<23 kg/m2). Aromatase inhibitors (AIs) are more effective in postmenopausal women than tamoxifen but recent studies have observed a reduced efﬁcacy of adjuvant treatment with aromatase inhibitors relative to tamoxifen in patients with a high BMI . It has been suggested that the usual 1 mg per day dose of an AI such as anastrozole may not have the equivalent efﬁcacy in an obese patient compared to a lean patient . It is equally possible that the agonisteantagonist balance of activity of tamoxifen may be disrupted under conditions in which the BMI and hence estradiol levels are high . Although there is a modest disparity [33,34] between the levels of estrogen suppression observed as a result of treatment with different 3rd generation aromatase inhibitors, all achieve greater than 97% suppression of circulating estradiol. It has been demonstrated, using a sensitive estradiol assay, that in postmenopausal women with early breast cancer the residual levels of plasma estradiol and estrone sulphate, after treatment with letrozole or anastrozole, are related to BMI . Whether these modest but relatively higher residual levels of circulating estradiol in obese patients on treatment with an AI have any clinical signiﬁcance is unknown. However it is probable that the relationship between BMI and poor outcome in breast cancer is inﬂuenced by factors in addition to sex steroid levels. Obesity is known to have myriad metabolic consequences impacting on many metabolic and inﬂammatory mediators that may act in association with estrogens, or independently, to inﬂuence recurrence of disease. Successful Implementation of weight loss strategies in breast cancer patients with high BMI is likely to be more effective in inﬂuencing prognosis for patients than trying to speciﬁcally target the crosstalk between the many metabolic pathways that stimulate and drive the factors that result in a poor outcome for these patients, but such successful implementation faces substantial challenges. Hormones and gene expression Estradiol and progesterone, acting through cognate receptors, have an important role in breast development particularly at puberty, pregnancy and lactation. A recent publication by Pal et al. described how the mammary epigenome can change in response to changes in hormonal stimuli and in particular the possibility that the high levels of progesterone during pregnancy act to promote histone methylation and hence modify gene activity . Histone methylation has been implicated in silencing the expression of tumor suppressor genes and this suggests that sustained progesterone exposure could have a role in oncogenesis through disruption of the normal balance of the methylation of chromatin and speciﬁc gene expression. Other studies have indicated that serum estradiol levels can feedback at a genetic level, inﬂuencing the expression of estrogen sensitive genes in breast tissue . Importantly this behavior suggests that there could be a functional link between the clinical expression of some breast cancers and hormone levels and this is likely to be an important factor in the progression of disease. Dunbier et al. demonstrated, in postmenopausal women, a significant association between plasma estradiol levels and gene expression of known estrogen responsive genes (trefoil factor 1 (TFF1), growth regulation by estrogen in breast cancer 1 (GREB1), PDZ domain containing 1 (PDZK1) and progesterone receptor (PGR)) in ER-positive breast tumors . Haakensen et al., looking at normal breast tissue and carcinomas also identiﬁed genes associated with serum estradiol levels . The genes identiﬁed were associated with estradiol signaling, breast carcinogenesis and mammographic density. All had contrasting expression proﬁles in normal tissue compared with that observed in tumors, with the gene expression in the tumors from women with low circulating estradiol levels resembling that observed in normal tissue. Intratumoral levels of estrogens have also been found to correlate with the tumor gene expression of enzymes responsible for estrogen metabolism and the estrogen receptor gene (ESR1) . In a recent paper it has been demonstrated that in premenopausal women, the level of expression of estrogen regulated genes in endocrine responsive tumors may be linked with normal cyclical changes in circulating hormone levels during the menstrual cycle . Haynes et al. demonstrated that the expression of estrogen responsive genes (PGR, GREB1, TFF1 and PDZK1) was higher at times in the menstrual cycle when the estrogen levels would be expected to be high and low when estrogen levels would be at their nadir . An increasing drive toward personalized treatments for breast cancer has led to considerable clinical interest in identifying ER positive tumors that will beneﬁt from endocrine therapy from those less endocrine responsive cancers that might beneﬁt from an alternative therapeutic approach. If the expression of responsive genes is affected by circulating hormone levels then measurements of sex hormones may ultimately provide a marker for endocrine sensitivity, and hence disease outcome, after treatment with endocrine agents. Inﬂuence of sex steroids on breast cancer progression Approximately 80% of breast cancers are estrogen receptor positive and the large majority of these tumors are inﬂuenced by plasma estrogens to some degree. However few studies have been E. Folkerd, M. Dowsett / The Breast 22 (2013) S38eS43 conducted looking for direct evidence for a relationship between sex steroids and outcome of treatment although Lønning et al. have reported that time to progression was shorter in breast cancer patients who had the highest estrogen levels . The inﬂuence of sex hormones on breast cancer progression is evident from the beneﬁts derived from hormone withdrawal treatment and especially the evidence of a correlation of completeness of hormone withdrawal with clinical beneﬁt. In contrast to the ﬁrst and second generation inhibitors such as aminoglutethimide and fadrozole which inhibited estradiol production by 90%, third generation inhibitors, letrozole, anastrozole and exemestane all inhibit by more than 97% and are more effective at minimizing progression of disease in the adjuvant setting [33,34]. Tumors differ however in their relative initial responsiveness to sex steroids and further, after long-term estrogen deprivation may become sensitized to residual levels of estrogens and progress [42,43]. Treatment regimes are being developed to attempt to gain longer-term remissions and slow progression to advanced disease by targeting the interactions between resistance mechanisms and the estrogen receptor. It is probable that such strategies may be most effective when given in combination with an AI. It is the studies linking sex steroid levels with gene expression proﬁles that are starting to unravel the complexities of breast cancer biology. This is particularly important where it relates to signaling and the molecular factors that contribute to the variable response of ER-positive tumors to hormone stimulation and hence to predicting beneﬁt from estrogen deprivation therapy. It is in this area of research that advances are likely to be made that translate in the clinical setting to the limitation of disease progression. Estrogen, mammographic density and breast cancer prevention Mammographic density, which is a measure of the relative amount of stroma and glandular tissue, is a notable risk factor for breast cancer incidence  and possibly progression . Women with the densest breasts have a risk four to six times greater than those with the most lucent. It is possible that hormone exposure is an inﬂuence on mammographic density because density changes in response to treatment with tamoxifen, with exogenous hormonal inﬂuences such as HRT and also at the time of the menopause. However the ﬁndings of studies examining the relationship between pre- and postmenopausal estrogen levels and mammographic density have been inconsistent. Walker et al. measuring sex hormone levels across the menstrual cycle found modest associations of urinary estrone glucuronide with mammographic density . A cross sectional analysis of data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial found that higher levels of estrone, estradiol and free estradiol were related to mammographic density . However in a large cross sectional study of postmenopausal women from the European Prospective Investigation into Cancer and Nutrition (EPIC) where serum levels of 7 sex hormones (estradiol, testosterone, SHBG, androstenedione, 17-OH-progesterone, estrone and estrone sulphate) were compared with mammographic density there were no associations with hormones other than a weak positive association with SHBG levels (p ¼ 0.09) . Similarly in a study of mammographic density in Afro-Caribbean women and Caucasian women, there were no associations observed between these biomarkers and mammographic density after controlling for the effect of BMI. The authors suggest that mammographic density may be inﬂuenced by sex hormones but the crucial period of exposure may be during the premenopausal years when the circulating steroid levels are much higher . The results suggest that mammographic density and sex hormones may be independent predictors of breast cancer risk S41 and as such could be used together to formulate an algorithm of breast cancer risk in postmenopausal women. Women identiﬁed at high risk according to the predictors in the algorithm could be monitored and advised on strategies for lowering risk. The utility of the measurement of low concentrations of estradiol Estradiol measurements have always been an important tool for deﬁning menopausal status. In this regard modern treatments for breast cancer have afforded new situations where estradiol measurements are valuable. For women taking aromatase inhibitors, estradiol measurements can be used to demonstrate applicability, compliance and efﬁcacy. Estradiol measurements have also been used in many epidemiology studies looking at a range of diseases such as osteoporosis and many diverse hormonally driven cancers, but particularly in the evaluation of breast cancer risk and in the development of risk reduction strategies. Speciﬁc instances where the measurements of circulating estradiol are advantageous are considered in more detail below. 1. As an indicator of ovarian function The standard treatment for women with early ERþ breast cancer is surgery followed by chemotherapy if necessary and then hormone therapy, tamoxifen for premenopausal women and aromatase inhibitors for postmenopausal women. As such the assessment of menopausal status is a determinant of treatment. Treatment with aromatase inhibitors is very effective in postmenopausal women with hormone sensitive breast cancer leading to substantial beneﬁt in disease outcome [50,51]. However in premenopausal women who have become amenorrheic following chemotherapy the profound inhibition of estrogen production as a result of treatment with an AI can act on the hypothalamicepituitary axis resulting in a stimulation of gonadotrophin secretion and a return of ovarian function. It is therefore important to verify menopausal status with measurements of gonadotrophins and also estradiol using methodology sensitive enough to quantitate estradiol at levels to 10 pmol/l or below, before deciding on appropriate hormone therapy and for a period after administration of an AI [52,53]. 2. Vaginal estrogens In postmenopausal women AIs are used as adjuvant therapy in the treatment of hormone sensitive breast cancer. These agents inhibit the activity of the enzyme responsible for the peripheral conversion of androgens to estrogens decreasing circulating estrogen levels from around 10e60 pmol/l to below 3 pmol/l. The profound estrogen suppression that occurs as a result of AI treatment can lead to the development of atrophic vaginitis. This condition is associated with urinary incontinence, dyspareunia, dryness and pain leading to a diminished quality of life. Treatment with systemic estrogen replacement therapy is contraindicated but the use of localized vaginal estrogen preparations such as creams, rings or tablets with minimal systemic absorption can provide symptomatic relief in this setting. However it has been reported that the use of vaginal estrogens can signiﬁcantly raise systemic estrogen levels thereby reversing the suppression achieved by AIs in women with breast cancer . Any ‘spill over’ effect has been reported by some to be transitory and linked to the degree of maturation of the vaginal epithelium. However, if vaginal estrogens are administered in combination with AIs, even for a limited duration, it is important to monitor the plasma estradiol levels using a sensitive estrogen assay so that a judgment can be made as to whether the efﬁcacy of the AI is being compromised. S42 E. Folkerd, M. Dowsett / The Breast 22 (2013) S38eS43 Standardization of estradiol assays Consideration of the utility of measuring circulating estradiol levels particularly at the low concentrations found in postmenopausal women and women taking aromatase inhibitors necessitates a discussion of the problems of methodology. One of the major impediments to the use of estradiol measurements to predict risk both in epidemiology studies and the putative use in risk algorithms is the lack of robust technology for the quantiﬁcation of estradiol in the range commonly found in postmenopausal women (10e60 pmol/l). Monitoring effectiveness of AI treatment needs yet more sensitive assays. This has been discussed in detail elsewhere [55,56] but for immunoassays, accuracy relies on pre-puriﬁcation of the estradiol to disassociate the steroid from SHBG and eliminate interferences from water soluble conjugated steroids. There is no doubt that the lack of sensitivity and antibody speciﬁcity in many of the currently available assays reduce the capacity for accurate interpretation and limit the prognostic detail leading to widespread inconsistencies and erroneous conclusions. Mass spectrometry is the emerging technology for estradiol analyses but it is by no means deﬁnitive as yet. There appear to be as many between laboratory differences in equipment, methodology and results obtained using mass spectrometry as there are between laboratories using immunoassay techniques. The term ‘gold standard’ cannot be applied to estradiol measurements made by mass spectrometry until there is a consensus on quality . Unless the procedures for estradiol measurement improve such that excellence is easily achievable with a widely available technology or there is a collective will to standardize measurements it is difﬁcult to see how the current situation will improve. Conﬂict of interest statement MD has received consultancy and research grants from Astra Zeneca, and a research grant from Novartis. Acknowledgments We would like to thank the Royal Marsden National Institute for Health Research Biomedical Research Centre and Breakthrough Breast Cancer for their support. References  Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet 1896;148:162e5.  Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet 2003;361: 296e300.  Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, et al. 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Standardization of steroid hormone assays: why, how and when? Cancer Epidemiol Biomarkers Prev 2007;16: 1713e9. The Breast 22 (2013) S44eS47 Contents lists available at SciVerse ScienceDirect The Breast journal homepage: www.elsevier.com/brst Obesity and endocrine therapy: Host factors and breast cancer outcome Pamela J. Goodwin a, b, * a Department of Medicine, Division of Medical Oncology and Hematology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada b Division of Clinical Epidemiology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada a b s t r a c t Keywords: Breast cancer Adjuvant Body mass index Aromatase inhibitor Effectiveness Obesity is becoming increasingly prevalent and it has been linked to poor breast cancer outcomes. Because obesity is associated with increased adipose tissue mass and aromatase activity [the target of aromatase inhibitors (AIs)], there is concern that these agents may be less effective in women who are overweight or obese. Four of the randomized trials of AIs vs. tamoxifen conducted in the adjuvant breast cancer setting (ATAC, BIG 1-98 and TEAM in the postmenopausal setting and ABCSG-12 in the premenopausal setting) have reported effects of body mass index (BMI) on the relative effectiveness of an AI vs. tamoxifen. Obesity was conﬁrmed as an adverse prognostic factor in ATAC and BIG 1-98 but not the TEAM study; in ABSCG-12, obesity was associated with poor outcomes in the anastrozole arm only. In the three postmenopausal trials, the use of an AI vs. tamoxifen was associated with better outcomes at all levels of BMI [all hazard ratios for recurrence <1, although 95% conﬁdence intervals often included 1 due to lower power and smaller reductions in risk]. Of note, there was no signiﬁcant interaction of BMI with letrozole (vs. tamoxifen) in the BIG 1-98 trial; while ATAC investigators concluded that the relative beneﬁt of anastrozole (vs. tamoxifen) might be better in thinner (vs. heavier) women. In ABCSG-12, the use of anastrozole (vs. tamoxifen) was associated with signiﬁcantly worse outcomes in women with BMI 25 kg/m2 (similar to the detrimental effect of anastrozole on overall survival seen in the parent trial). These ﬁndings do not support the use of BMI as a predictor of AI (vs. tamoxifen) beneﬁt in the adjuvant setting in postmenopausal breast cancer. Ó 2013 Elsevier Ltd. All rights reserved. Introduction Overweight and obesity are becoming increasingly prevalent in adult populations in most of the developed world. The association of body mass index [BMI ¼ weight (kg)/height (m)2] with breast cancer outcomes has been examined in over 50 studies. A recent meta-analysis  has reported a hazard ratio (HR) of 1.30e1.35 for mortality in obese vs. non-obese subjects; this association was seen whether obesity was measured as BMI or waist-to-hip ratio, in preand postmenopausal women, and in women diagnosed prior to or after the widespread use of anthracyclines and taxanes in the adjuvant setting. Our group  has shown that prognostic associations of obesity for breast cancer speciﬁc and overall survival are similar in women with hormone receptor positive vs. hormone receptor negative tumors, although some individual studies have yielded discordant results . * Mount Sinai Hospital, 1284-600 University Avenue, Toronto, Ontario M5G 1X5, Canada. Tel.: þ1 416 586 8605; fax: þ1 416 586 8659. E-mail address: [email protected] 0960-9776/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2013.07.008 How could obesity impact biologic processes and aromatase inhibitor activity? Obesity is a complex physiologic state that is associated with metabolic changes including hyperinsulinemia, hyperglycemia, hyperlipidemia, altered adiopokine proﬁle (higher leptin and lower adiponectin) and generalized inﬂammation . Perhaps of greatest relevance to breast cancer is the association of adiposity with higher estrogen levels in postmenopausal women. In these women, aromatization of androstenedione and testosterone to estrone and estradiol in adipose tissue is the major source of estrogen (in contrast to an ovarian source in premenopausal women). An increasing volume of adipose tissue in obesity is associated with an increase in total body aromatase activity. Increasing age and higher leptin levels have also been associated with higher aromatase activity [5,6]. In mice, obesity-associated inﬂammation is associated with increased aromatase activity in breast tissue . It is also possible that non-estrogen related physiologic changes in obesity may be relevant in breast cancer. For example, higher insulin levels, P.J. Goodwin / The Breast 22 (2013) S44eS47 associated with poorer breast cancer outcomes , may activate fetal insulin/IGF-1 receptors on breast cancer cells to stimulate signaling through PI3K and RaseRaf pathways. Cross-talk exists between IGF-1/insulin signaling pathways and estrogenic signaling pathways; enhanced signaling through the insulin IGF-1 pathway in obese women may activate estrogen signaling pathways , a mechanism that is of particular concern in the absence of estrogen receptor blockade by tamoxifen. A recent report from the Women’s Health Initiative that insulin may be a more important mediator of obesity-associated postmenopausal breast cancer risk than estradiol  lends support to this concern. In postmenopausal women, BMI is signiﬁcantly correlated with serum levels of estrone and estradiol (r ¼ 0.38, p < 0.001 and r ¼ 0.41, p < 0.001 respectively) ; this is important as blood levels of estradiol, bioavailable estradiol and free estradiol have been associated with increased risk of breast cancer recurrence [HR 1.41, 95% Conﬁdence Interval (CI) 1.01e1.97; HR 1.26, 95% CI 1.03e1.53; HR 1.31, 95% CI 1.03e1.65 per unit increase in log concentration, respectively] . This has raised concerns that aromatase inhibitors (AIs), which target the aromatase enzyme to lower blood estrogen levels, may be have reduced effectiveness in postmenopausal women who are overweight or obese. AIs have been shown to lower plasma estradiol, estrone and estrone sulfate levels in postmenopausal women by up to 99%; there is some evidence that letrozole may be more effective than anastrozole in this regard . Emerging evidence suggests that suppression of estrone and estradiol by anastrozole and letrozole may be less complete in overweight and obese women [14,15]. The clinical relevance of these observations is unclear given that major levels of suppression were identiﬁed even in obese women. Furthermore, it is unclear whether a higher dose of an AI might lead to greater aromatase suppression in heavier women; one recent report suggests that plasma letrozole levels are lower in women with higher BMI, lending some support to more individualized dosing of AIs . AIs in the adjuvant breast cancer setting e What do we know about the impact of BMI? The potential for BMI to impact AI efﬁcacy is an important consideration as randomized trials have demonstrated beneﬁts of the three commonly available anti-estrogens (letrozole, anastrozole and exemestane) over tamoxifen on disease (or recurrence) free survival in postmenopausal women; evidence of overall survival beneﬁts is emerging. Together, these results have led to current American Society of Clinical Oncology (ASCO) Practice Guidelines  which recommend that “Postmenopausal women with hormone receptor positive breast cancer consider incorporating AI therapy at some point during adjuvant treatment, either as up front or as sequential treatment after tamoxifen”. At least four of the randomized trials (ATAC, BIG 1-98, TEAM, ABCSG-12) comparing an AI to tamoxifen in the adjuvant breast cancer setting have explored the effect of BMI on treatment efﬁcacy [18e21]. A brief summary of the overall clinical results of these trials is shown in Table 1. With the exception of ABCSG-12 , each was conducted in postmenopausal women and two showed a beneﬁt for the AI (in comparison to tamoxifen alone) in terms of recurrence/ disease-free survival. The fourth trial, ABCSG-12 , was conducted in premenopausal women e anastrozole combined with goserelin (to suppress ovarian function) was compared to tamoxifen combined with goserelin and half the subjects received zoledronic acid (ZA). ZA improved disease-free survival, however, overall survival was lower in those receiving anastrozole (HR 1.75, 95% CI 1.08e2.83). In the original publication of the ATAC trial , inclusion of BMI in a Forrest plot revealed that a BMI <26.7 kg/m2 was associated S45 Table 1 Trials of aromatase inhibitors vs. tamoxifen by BMI. Trial Comparison(s) Overall breast cancer results ATAC  A vs. T BIG 1-98  L vs. T vs. L / T vs. T/L E vs. T / E A þ G vs. T þ G A better than T (DFS, TTR, TTDR, contralateral BC, not OS) L better than T (DFS, DDFS, OS) L / T or T / L ¼ L E ¼ T / E (DFS, RFS, DDFS, OS) A þ G worse than T þ G (OS) A þ G ¼ T þ G (DFS) TEAM  ABCSG-12  (premenopausal) Abbreviations: BMI, body mass index; A, Anastrozole; T, Tamoxifen; L, Letrozole; E, Exemestane; G, Goserelin; DFS, Disease-free survival; DDFS, Distant disease-free survival; TTR, Time to recurrence; TTDR, Time to distant recurrence; BC, breast cancer; RFS, Relapse-free survival; OS, overall survival. with a non-signiﬁcantly greater relative beneﬁt for anastrozole (vs. tamoxifen) on time to recurrence compared to a BMI >26.75 kg/m2. This was explored in greater detail in a recent publication  in which higher BMI was associated with a higher risk of recurrence in the overall study population and in those randomized to anastrozole (BMI >35 vs. < 23 kg/m2 HR 1.53, 95% CI 1.01e2.32, p ¼ 0.001); a similar pattern was not seen in those randomized to tamoxifen (comparable HR 1.18, 95% CI 0.90e1.84, p ¼ 0.23, p interaction 0.04). When the relative efﬁcacy of anastrozole vs. tamoxifen was examined by BMI category (<23, 23e25, 25e28, 28e30, 30e35, >35 kg/m2), HRs for all recurrences (and for distant recurrences separately) were below 1 for all BMI categories (favoring anastrozole), however, HRs were numerically smaller when BMI was lower, a ﬁnding interpreted by the authors as “the relative beneﬁt of anastrozole vs. tamoxifen was non-signiﬁcantly better in thin women compared to overweight women”. The authors reported that the effects of tamoxifen were similar across BMI categories (p ¼ 0.54) while those of anastrozole were lower in women with higher BMI (p ¼ 0.01). BIG 1-98 investigators  examined BMI associations in the two monotherapy arms of the four arm parent trial (i.e. tamoxifen for 5 years vs. letrozole for 5 years). Combining these 2 arms, a signiﬁcant adverse association of higher BMI with overall survival (p ¼ 0.003) was identiﬁed; a non-signiﬁcant association of obesity with distant recurrence (p ¼ 0.12) but not with breast cancer recurrence (p ¼ 0.81) was also reported. There was no evidence of a signiﬁcant interaction of BMI with the relative efﬁcacy of letrozole vs. tamoxifen (interaction p ¼ 0.74). HRs comparing letrozole to tamoxifen ranged from 0.68 to 0.82 for all BMI subgroups (<25, 25<30, 30 kg/m2) for all outcomes (disease-free survival, overall survival, breast cancer free interval or distant recurrence free interval), reﬂecting better outcomes with letrozole over the range of BMI. In the TEAM trial , tamoxifen for 2.5 years followed by exemestane for 2.5 years was compared to exemestane monotherapy for ﬁve years. At 2.75 years (comparing exemestane to tamoxifen prior to switching), there was a borderline increased risk of relapse in obese women receiving tamoxifen (12.5% vs. 9.1% in normal weight, p ¼ 0.06) but not in those receiving exemestane (12.5% vs. 9.1%, p ¼ 0.57). At 5.1 years BMI was not associated with risk of relapse in either arm. When the relative efﬁcacy of exemestane vs. tamoxifen on risk of relapse was examined at 2.75 years, HRs favored exemestane for all BMI categories and a significant beneﬁt was seen in women with BMI >30 kg/m2 (HR 0.57, 95% CI 0.39e0.84). At 5.1 years, comparing exemestane monotherapy to a tamoxifen to exemestane switch, HRs for relapse free or overall survival favored exemestane for all BMI categories, although 95% CIs included 1 for all comparisons. ABCSG-12  differs from the other trials in that it was conducted in premenopausal women. All women received goserelin to S46 P.J. Goodwin / The Breast 22 (2013) S44eS47 Table 2 Aromatase inhibitor efﬁcacy in the adjuvant setting: BMI effects. Trial Comparison N (BMI) Follow up (BMI) Prognostic associations of higher BMI Predictive effects by BMI ATAC  A vs. T (post) 4939 36.7% OW 27.3% OB 8.3 yrs All subjects e adverse (RFS, DDFS, BCSS) BIG 1-98  L vs. T (post) 4760 36% OW 23% OB 8.7 yrs TEAM  E vs. T / E (post) 4700 36.9% OW 23.3% OB (exclude if BMI < 18.5) 2.75 yrs 5.1 yrs All subjects e adverse (DFS, DDFS, OS, n/s) OS: Obese vs. Normal HR 1.18 Tamoxifen HR 1.21 Letrozole 2.75 yrs e trend to adverse in T (p ¼ 0.06) but not A (p ¼ 0.57) 5.1 yrs e no association in E or T A better than T at all BMI levels A less effective when BMI 30 for DDFS (p heterogeneity 0.01) Relative beneﬁt of A vs. T better when BMI low (p ¼ n/s) Treatment by BMI interactions not signiﬁcant L vs. T e HR 0.77 NW, 0.68 OW, 0.78 OB ABCSG 12  A vs. T (þgoserelin) (pre) 1684 23.2% OW 10.8% OB 5.2 yrs A e adverse (DFS, OS) T e no association E better than T (2.5 yrs) at all BMI levels, signiﬁcant in BMI >30 (DDFS HR 0.57, 95% CI 0.39e0.84) E better than T / E (5.1 yrs) for any BMI (n/s), BMI > 30 (DDFS HR 0.75, 95% CI 0.56e1.01 and OS HR 0.71, 95% CI 0.51e1.01) BMI <25: A ¼ T e (DFS, OS) BMI 25: A worse than T HR 1.49, 95% CI 0.93e2.03 DFS HR 3.03, 95% CI 1.35e6.82 OS Abbreviations: A, Anastrozole; T, Tamoxifen; L, Letrozole; E, Exemestane; NW, normal weight; OW, overweight; OB, obese; BMI, body mass index; RFS, recurrence-free survival; DDFS, distant disease-free survival; DFS, disease-free survival; BCSS breast cancer-speciﬁc survival; OS, overall survival; n/s, not stated; HR, hazard ratio; CI, conﬁdence interval. suppress ovarian function and were then randomized to receive tamoxifen vs. anastrozole (half were also randomized to zoledronic acid). Prior research  had demonstrated these approaches reduced estradiol levels and, in the case of anastrozole plus goserelin, led to increases in FSH, consistent with ovarian suppression. A beneﬁt of anastrozole over tamoxifen (both with goserelin) was not identiﬁed in this trial, in fact, overall survival was worse in those receiving anastrozole (vs tamoxifen) (HR 1.75, 95% CI 1.08e2.83). Overweight and obese subjects receiving anastrozole had an increased risk of disease recurrence (HR 1.60, 95% CI 1.06e2.41) and a signiﬁcantly increased risk of death (HR 2.14, 95% CI 1.17e3.92); a similar pattern was not seen in those receiving tamoxifen (HR 0.94, 95% CI 0.60e1.64 and HR 0.83, 95% CI 0.35e1.93 respectively) . In keeping with the results of the parent trial, in women with BMI >25 kg/m2, the use of anastrozole plus goserelin, compared to tamoxifen plus goserelin, was associated with non-signiﬁcantly worse disease-free survival (HR 1.49, 95% CI 0.93e2.38) and significantly worse overall survival (HR 3.03, 95% CI 1.35e6.82). These observations are summarized in Table 2. It can be seen that there is little evidence that obesity is associated with signiﬁcantly reduced aromatase inhibitor efﬁcacy (compared to tamoxifen) in the three trials conducted in postmenopausal women. In the ABCSG-12 trial , conducted in premenopausal women, with the addition of goserelin to anastrozole or tamoxifen, there was some evidence of worse outcomes in women with BMI >25 kg/m2 when anastrozole plus goserelin was administered. Two early trials [25,26] explored AI efﬁcacy in relation to BMI in the advanced breast cancer setting. Michaud et al.  found no evidence that BMI was associated with relative beneﬁt of anastrozole over tamoxifen with respect to time to disease progression or response rates. Schmid et al.  compared letrozole 0.5 mge 2.5 mg and found no signiﬁcant differences in overall response rates (ORR) in women with BMI below and above and below 30 kg/ m  although in subgroup analyses of women with dominant visceral metastases (with or without concomitant bone metastases) those who received letrozole 2.5 mg had a higher ORR if their BMI was <30 vs >30 kg/m2. Finally, in a neoadjuvant study , women with high BMI had higher rates of response (WHO criteria)  to exemestane than those with lower BMI (60.0% when BMI 25 kg/ m2 vs. 56.0% when BMI was 22e25 kg/m  and 21.7% when BMI was below 22 kg/m ). These results persisted in multivariate analyses e they do not lend support to the hypothesis that high BMI is associated with lower AI beneﬁt. Conclusions Despite observational evidence suggesting that suppression of aromatase activity by AIs may be less complete in heavy postmenopausal women, evidence from randomized trials conducted in the adjuvant and metastatic settings provides little evidence that this leads to clinically worse outcomes, at least in postmenopausal women. The available evidence suggests that the use of AIs (particularly letrozole as evidenced by the BIG 1-98 results) vs. tamoxifen in these women is associated with better breast cancer outcomes, regardless of BMI, although relative beneﬁts may be smaller in overweight and obese women. Put in other words, although higher BMI may be associated with prognosis in early breast cancer, the current evidence does not suggest it is signiﬁcantly predictive of AI beneﬁt over tamoxifen. Because power to examine treatment effects by BMI category was low in individual trials, consideration should be given to further exploring these issues in meta-analyses using individual patient data. It should be noted that treatment selection is based not only on efﬁcacy, but also on toxicity [29,30]. As a result, such meta-analyses would ideally also investigate the balance of risks and toxicities of AIs (vs. tamoxifen) across BMI categories. One report  has suggested that AI associated joint symptoms are more severe in obese women (possibly reﬂecting mechanical factors). The use of AIs may be associated with increased cardiovascular risk  and this risk may be greatest in heavier women. Thus, the net beneﬁt of AI vs. tamoxifen may be lower in heavier women. 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