Obesity and cancer: the risks, science, and potential management strategies

Overweight and obesity increase the risk of developing several cancers. Once cancer develops, individuals may be at increased risk of recurrence and poorer survival if they are overweight or obese. A statistically significant association between overweight or obesity and breast cancer recurrence or survival has been observed in the majority of population-based case series; however, adiposity has been shown to have less of an effect on prognosis in the clinical trial setting. Weight gain after breast cancer diagnosis may also be associated with decreased prognosis. New evidence suggests that overweight/obesity vs normal weight may increase the risk of poor prognosis among resected colon cancer patients and the risk of chemical recurrence inprostate cancer patients. Furthermore, obese cancer patients are at increased risk for developing problems following surgery, including wound complication, lymphedema, second cancers, and the chronic diseases affecting obese individuals without cancer such as cardiovascular disease and diabetes. Mechanisms proposed to explain the association between obesity and reduced prognosis include adipose tissue-induced increased concentrations of estrogens and testosterone, insulin, bioavailable insulin-like growth factors, leptin, and cytokines. Additional proposed mechanisms include reduced immune functioning, chemotherapy dosing, and differences in diet and physical activity in obese and nonobese patients. There have been no randomized clinical trials testing the effect of weight loss on recurrence or survival in overweight or obese cancer patients, however. In the absence of clinical trial data, normal weight, overweight, and obese patients should be advised to avoid weight gain through the cancer treatment process. In addition, weight loss is probably safe, and perhaps helpful, for overweight and obese cancer survivors who are otherwise healthy.     

Favorable modulation of benign breast tissue and serum risk biomarkers is associated with >10 % weight loss in postmenopausal women

We conducted a phase II feasibility study of a 6-month behavioral weight loss intervention in postmenopausal overweight and obese women at increased risk for breast cancer and the effects of weight loss on anthropomorphic, blood, and benign breast tissue biomarkers. 67 women were screened by random peri-areolar fine-needle aspiration, 27 were registered and 24 participated in the interventional phase. The 24 biomarker evaluable women had a median baseline BMI of 34.2 kg/m² and lost a median of 11 % of their initial weight. Significant tissue biomarker modulation after the 6-month intervention was noted for Ki-67 (if restricted to the 15 women with any Ki-67 at baseline, p = 0.041), adiponectin to leptin ratio (p = 0.003); and cyclin B1 (p = 0.001), phosphorylated retinoblastoma (p = 0.005), and ribosomal S6 (p = 0.004) proteins. Favorable modulation for serum markers was observed for sex hormone-binding globulin (p < 0.001), bioavailable estradiol (p < 0.001), bioavailable testosterone (p = 0.033), insulin (p = 0.018), adiponectin (p = 0.001), leptin (p < 0.001), the adiponectin to leptin ratio (p < 0.001), C-reactive protein (p = 0.002), and hepatocyte growth factor (p = 0.011). When subdivided by <10 or >10 % weight loss, change in percent total body and android (visceral) fat, physical activity, and the majority of the serum and tissue biomarkers were significantly modulated only for women with >10 % weight loss from baseline. Some factors such as serum PAI-1 and breast tissue pS2 (estrogen-inducible gene) mRNA were not significantly modulated overall but were when considering only those with >10 % weight loss. In conclusion, a median weight loss of 11 % over 6 months resulted in favorable modulation of a number of anthropomorphic, breast tissue and serum risk and mechanistic markers. Weight loss of 10 % or more should likely be the goal for breast cancer risk reduction studies in obese women.     

The effect of weight-loss on estimated breast-cancer risk and sex-hormone levels

The effect of weight loss on estimated breast cancer risk, sex hormone binding globulin (SHBG), total and free estradiol levels was evaluated. Increasing weight loss reduced upper body fat distribution progressively. Women with a family history of breast cancer who lost more than 7.0 kilograms decreased their estimated breast cancer risk by 25.7% while women without such a family history decreased their risk by 42.8%. A significant (P<0.001) increase in SHBG with a 4.0 to 7.4 kg weight loss was seen in both pre and postmenopausal women (P<0.05). No significant change in total or free estradiol levels was observed.     

Racial/ethnic differences in postmenopausal endogenous hormones: the multiethnic cohort study.

Postmenopausal women with increased estrogens and lowered sex hormone-binding globulin (SHBG) concentrations are at increased risk of breast cancer. In the Multiethnic Cohort Study, the highest incidence rates of postmenopausal breast cancer were observed among Native Hawaiians followed by Japanese Americans, Whites, African Americans, and Latinas. Ethnic differences in endogenous sex hormone profiles may contribute to some of the variation in breast cancer incidence. Plasma concentrations of androstenedione, testosterone, estrone (E(1)), estradiol (E(2)), and SHBG were measured in 739 postmenopausal women from the Multiethnic Cohort Study (240 African Americans, 81 Native Hawaiians, 96 Japanese Americans, 231 Latinas, and 91 Whites). After adjusting for age, known breast cancer risk factors and lifestyle factors, the mean levels of testosterone, estrogen, and SHBG varied across populations (Ps < or = 0.004). Across racial/ethnic groups, Native Hawaiians had the highest mean levels of androstenedione, testosterone, and estrogens and the lowest mean levels of SHBG. Compared with Whites, Native Hawaiians had higher androstenedione (+22%, P = 0.017), total testosterone (+26%, P = 0.013), bioavailable testosterone (+33%, P = 0.002), E(1) (> or =21%; P = 0.009), total E(2) (+26%, P = 0.001), bioavailable E(2) (+31%, P < 0.001), and lower SHBG (-12% P = 0.07) levels. Compared with Whites, Japanese Americans had higher E(2) (+15%, P = 0.036) and bioavailable E(2) (+18%, P = 0.024) levels. African Americans also had higher E(1) (+21%, P = 0.004), E(2) (+20%, P = 0.007), and bioavailable E(2) (+20%, P = 0.015) levels compared with Whites, whereas mean levels in Latinas were similar to those of Whites. Many of the differences in endogenous postmenopausal hormonal milieu across these five racial/ethnic groups are consistent with the known differences in breast cancer incidence across these populations.     

Relationships between circulating hormone levels, mammographic percent density and breast cancer risk factors in postmenopausal women

Background Endogenous hormones and insulin-like growth factors (IGF) play a central role in breast cancer development. Mammographic density, an important breast cancer risk factor, has been associated with these biomarkers in premenopausal women. The aim of this study was to assess the relationships between circulating hormones, clinical features related to breast cancer risk and mammographic density in postmenopausal women. Subjects and methods The study included 226 postmenopausal women participating in a clinical prevention trial. We performed baseline measurements of mammographic percent density and circulating levels of estradiol, sex-hormone binding globulin (SHBG), follicle stimulating hormone (FSH), prolactin, C-terminal cross-link telopeptide, IGF-I, and IGF binding protein-3. Results Median age and time since last menses were 52 years and 15 months, respectively. Median body mass index was 24.1 kg/m². After adjusting for age and body mass index, estradiol was the only biomarker significantly correlated with mammographic density (r = 0.17; P = 0.04). Women with normal body mass index had higher mammographic density (P < 0.001), higher SHBG (P < 0.0001), higher FSH (P = 0.002) and lower estradiol levels (P = 0.01) than those who were overweight. Women who had previous biopsies for benign breast disease had a higher mammographic density (P = 0.006). Conclusions In these recently postmenopausal women, mammographic percent density is directly associated with circulating estradiol levels. Our results provide further support to the role of circulating hormones in breast cancer risk.     

Premenopausal endogenous steroid hormones and breast cancer risk: results from the Nurses' Health Study II

Introduction

Prior research supports an association between endogenous sex steroids and breast cancer among postmenopausal women; the association is less clear among premenopausal women.

Methods

We evaluated the associations between estrogens, androgens, progesterone and sex hormone binding globulin (SHBG) and breast cancer in a nested case-control study in the Nurses'' Health Study II. Between 1996 and 1999, 29,611 participants provided blood samples; 18,521 provided samples timed in early follicular and mid-luteal phases of the menstrual cycle. A total of 634 women, premenopausal at blood collection, developed breast cancer between 1999 and 2009 and were matched to 1,264 controls (514 cases and 1,030 controls with timed samples). We used conditional logistic regression controlling for breast cancer risk factors for overall analyses; unconditional logistic regression additionally controlling for matching factors was used for subgroup analyses.

Results

In analyses of premenopausal estrogens including breast cancers diagnosed both before and after menopause, there was no association between follicular estradiol, estrone and free estradiol and risk of either total or invasive breast cancer. Luteal estradiol was positively associated with estrogen receptor positive (ER+)/progesterone receptor positive (PR+) cancers (5^th vs. 1^st quintile odds ratio (OR): 1.7 (95% confidence interval (CI): 1.0 to 2.9), P_trend = 0.02). Luteal estrone, free estradiol and progesterone were not associated with risk. Androgens were suggestively or significantly associated with risk when the sample was restricted to invasive tumors (for example, testosterone: OR: 1.4 (1.0 to 2.0), P_trend = 0.23) and ER+/PR+ disease (testosterone: OR: 1.7 (1.1 to 2.6) P_trend = 0.10; dehydroepiandrosterone sulfate (DHEAS) OR: 1.3 (0.8 to 2.0) P_trend = 0.05). SHBG was not associated with breast cancer risk. The results varied by menopausal status at diagnosis, with follicular estradiol suggestively positively associated with breast cancers in women premenopausal at diagnosis (OR: 1.1 (0.9 to 1.3) and significantly inversely associated with postmenopausal disease (OR: 0.6 (0.4 to 0.9); P_{heterogeneity} < 0.01).

Conclusions

Androgens were associated with modestly increased risk of breast cancer in this population, with stronger associations for invasive and ER+/PR+ disease. Luteal phase estradiol levels were suggestively associated with ER+/PR+ tumors but no other strong associations were observed with estrogens. Associations with follicular phase estrogens may vary by menopausal status at diagnosis, but case numbers were limited. Additional studies to confirm the role of premenopausal hormones in the etiology of both premenopausal and postmenopausal breast cancer are needed.     

An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors

Insulin receptor substrate-1 (IRS-1) is a key downstream signaling molecule common to both the insulin and IGF signaling pathways that can interact with the estrogen pathway to regulate breast cell growth. We investigated whether a putative functional variant for IRS-1 (G972R) influences circulating levels of sex hormones, sex hormone binding globulin (SHBG), C-peptide, and insulin-like growth factor 1 (IGF-1) levels among post-menopausal African-American and non-Hispanic white breast cancer patients enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study. Circulating levels of sex hormones and growth factors can influence breast cancer recurrence and survival. Serum estrone, estradiol, testosterone, SHBG, IGF-1 and C-peptide were measured in 468 patients at 30+ months post diagnosis. Non-protein bound hormone levels (free estradiol, free testosterone) were calculated. In African-American patients, the IRS-1 variant was associated with increased serum levels of estrone (p=0.02), free estradiol (p=0.04), total testosterone (p=0.04), free testosterone (p=0.006) and decreased levels of sex hormone-binding globulin (p=0.02). No association was present for white patients. Our findings provide suggestive evidence that IRS-1 G972R variant may be associated with circulating levels of sex hormones and SHBG in African American breast cancer survivors.     

The impact of an aromatase inhibitor on body composition and gonadal hormone levels in women with breast cancer

Aromatase inhibitors (AIs) have become the standard adjuvant therapy of postmenopausal breast cancer survivors. AIs induce a reduction of bioavailable estrogens by inhibiting aromatase, which would be expected to induce alterations in body composition, more extensive than induced by menopause. The objectives are to examine the impact of AIs on (1) DXA-scan derived body composition and (2) gonadal hormone levels. This is a sub-analysis of a 2-year double-blind, placebo-controlled, randomized trial of 82 women with nonmetastatic breast cancer, newly menopausal following chemotherapy, who were randomized to risedronate (35 mg once weekly) versus placebo, and stratified for their usage of AI versus no AI. Outcomes included DXA-scan derived body composition and gonadal hormone levels. As a group, total body mass increased in women over 24 months. Women on AIs gained a significant amount of lean body mass compared to baseline as well as to no-AI users (P < 0.05). Women not on an AI gained total body fat compared to baseline and AI users (P < 0.05). Free testosterone significantly increased and sex hormone binding globulin (SHBG) significantly decreased in women on AIs compared to no AIs at 24 months (P < 0.01) while total estradiol and testosterone levels remained stable. Independent of AI usage, chemotherapy-induced postmenopausal breast cancer patients demonstrated an increase of total body mass. AI users demonstrated maintenance of total body fat, an increase in lean body mass and free testosterone levels, and a decrease in SHBG levels compared to no-AI users. The mechanisms and implications of these changes need to be studied further.     

Adiposity and sex hormones in postmenopausal breast cancer survivors.

PURPOSE: Overweight and obese women with breast cancer have poorer survival compared with thinner women. One possible reason is that breast cancer survivors with higher degrees of adiposity have higher concentrations of tumor-promoting hormones. This study examined the association between adiposity and concentrations of estrogens, androgens, and sex hormone-binding globulin (SHBG) in a population-based sample of postmenopausal women with breast cancer. METHODS: We studied the associations between body mass index (BMI), body fat mass, and percent body fat, measured by dual-energy x-ray absorptiometry scan, waist circumference, and waist-to-hip circumference ratio, with concentrations of estrone, estradiol, testosterone, SHBG, dehydroepiandrosterone sulfate, free estradiol, and free testosterone in 505 postmenopausal women in western Washington and New Mexico with incident stage 0 to IIIA breast cancer. Blood and adiposity measurements were performed between 4 and 12 months after diagnosis. RESULTS: Obese women (BMI > or = 30) had 35% higher concentrations of estrone and 130% higher concentrations of estradiol compared with lighter-weight women (BMI < 22.0; P =.005 and.002, respectively). Similar associations were observed for body fat mass, percent body fat, and waist circumference. Testosterone concentrations also increased with increasing levels of adiposity (P =.0001). Concentrations of free estradiol and free testosterone were two to three times greater in overweight and obese women compared with lighter-weight women (P =.0001). CONCLUSION: These data provide information about potential hormonal explanations for the association between adiposity and breast cancer prognosis. These sex hormones may be useful biomarkers for weight loss intervention studies in women with breast cancer.     

Does trauma or an intercurrent surgical intervention lead to a short-term increase in breast cancer recurrence rates?

BackgroundSeveral lines of evidence suggest that cytokines released as a result of wound healing might reactivate dormant breast cancer metastases. To test this, we examined if accidental trauma or surgery, unrelated to the original cancer, might stimulate the growth of dormant micrometastases and be related to an increase in the recurrence rate in the period after the event.MethodsTo test this hypothesis, we used data from the ATAC [Arimidex (anastrozole), tamoxifen alone or in combination] trial and coded the data for women who have experienced trauma or surgical procedures unrelated to the cancer. For the initial analysis, we considered recurrences occurring 2–24 months after the traumatic event and also between 2 and 12 months after trauma. In a secondary analysis, we also looked at recurrences in the first 2 months after event.ResultsThe hazard ratio (HR) for recurrence 2–24 months after event was 0.96 [confidence interval (CI) 0.86–1.07, P = 0.48]; for 2–12 months, it was 0.96 (CI 0.82–1.11, P = 0.58) and for 0–2 months, the HR was 0.87 (CI 0.54–1.38 P = 0.87).ConclusionTrauma was not associated with an increased rate of breast cancer recurrence in the 24-month window after the event in this large study.     

Effect of weight loss,with or without exercise,on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial

Introduction

Physical inactivity and overweight are risk factors for postmenopausal breast cancer. The effect of physical activity may be partially mediated by concordant weight loss. We studied the effect on serum sex hormones, which are known to be associated with postmenopausal breast cancer risk, that is attributable to exercise by comparing randomly obtained equivalent weight loss by following a hypocaloric diet only or mainly by exercise.

Methods

Overweight, insufficiently active women were randomised to a diet (N = 97), mainly exercise (N = 98) or control group (N = 48). The goal of both interventions was to achieve 5–6 kg of weight loss by following a calorie-restricted diet or an intensive exercise programme combined with only a small caloric restriction. Primary outcomes after 16 weeks were serum sex hormones and sex hormone-binding globulin (SHBG). Body fat and lean mass were measured by dual-energy X-ray absorptiometry.

Results

Both the diet (−4.9 kg) and mainly exercise (−5.5 kg) groups achieved the target weight loss. Loss of body fat was significantly greater with exercise versus diet (difference −1.4 kg, P < 0.001). In the mainly exercise arm, the reduction in free testosterone was statistically significantly greater than that of the diet arm (treatment effect ratio [TER] 0.92, P = 0.043), and the results were suggestive of a difference for androstenedione (TER 0.90, P = 0.064) and SHBG (TER 1.05, P = 0.070). Compared with the control arm, beneficial effects were seen with both interventions, diet and mainly exercise, respectively, on oestradiol (TER 0.86, P = 0.025; TER 0.83, P = 0.007), free oestradiol (TER 0.80, P = 0.002; TER 0.77, P < 0.001), SHBG (TER 1.14; TER 1.21, both P < 0.001) and free testosterone (TER 0.91, P = 0.069; TER = 0.84, P = 0.001). After adjustment for changes in body fat, intervention effects attenuated or disappeared.

Conclusions

Weight loss with both interventions resulted in favourable effects on serum sex hormones, which have been shown to be associated with a decrease in postmenopausal breast cancer risk. Weight loss induced mainly by exercise additionally resulted in maintenance of lean mass, greater fitness, greater fat loss and a larger effect on (some) sex hormones. The greater fat loss likely explains the observed larger effects on sex hormones.

Trial registration

ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01511276","term_id":"NCT01511276"}}NCT01511276. Registered on 12 January 2012.

Electronic supplementary material

The online version of this article (doi:10.1186/s13058-015-0633-9) contains supplementary material, which is available to authorized users.     

Maternal and cord blood hormone levels in the United States and China and the intrauterine origin of breast cancer

BackgroundBreast cancer is less common in China than in the United States and perinatal characteristics predict breast cancer risk in the offspring. We determined levels of pregnancy hormones in Boston and Shanghai to identify those possibly involved in the intrauterine origin of breast cancer.Participants and methodsWe compared maternal and cord blood levels of estradiol, estriol, testosterone, progesterone, prolactin, insulin-like growth factors (IGF) 1 and 2, insulin-like growth factor-binding protein 3, adiponectin and sex hormone-binding globulin (SHBG) in 241 Caucasian and 295 Chinese women.ResultsIn both centers, hormone levels at the 16th were predictive of those at the 27th gestational week, but there was little correlation between maternal and cord blood levels. In cord blood, we found significantly (P < 0.01) higher levels of estradiol (44.2%), testosterone (54.5%), IGF-2 (22.7%) and strikingly SHBG (104.6%) in Shanghai women, whereas the opposite was true for IGF-1 (-36.8%).ConclusionsTaking into account the current understanding of the plausible biological role of the examined endocrine factors, those likely to be involved in the intrauterine origin of breast cancer are SHBG and IGF-2, with higher cord blood levels among Chinese, and IGF-1, with higher cord blood levels among Caucasian women.     

The hormonal status indices and the risk of breast cancer

A case control study was carried out to assess relationship between certain hormonal indexes and risk of breast cancer. In premenopausal patients, blood plasma level of sex hormone-binding globulin (SHBG) was significantly higher while those of albumin-binding (bioavailable) and free estradiol were lower than in controls. No statistically significant difference in hormonal status parameters was established between menopausal patients and menopausal controls. However, concentrations of total, free and albumin-binding estradiol tended to be higher in breast cancer supporting the relationship between exposure of breast tissue to plasma free estradiol and risk of breast cancer. Unlike healthy females, menopausal breast cancer patients showed a decrease in SHBG level and a rise in free and albumin-binding estradiol concentration with age. SHBG level was inversely related to weight and Quetelet's index; however, the tendency reached statistical significance in the reproductive age group only.     

Effects of raloxifene on circulating prolactin and estradiol levels in premenopausal women at high risk for developing breast cancer.

BACKGROUND: Prolactin is a peptide hormone necessary for normal breast development that may contribute to breast tumorigenesis. Estrogen is a significant positive regulator of prolactin synthesis; therefore, raloxifene, a selective estrogen receptor modulator under study as a breast cancer prevention agent, may modulate both estradiol and prolactin levels by inhibiting estradiol from binding to its receptor. METHODS: Premenopausal women at increased risk for invasive breast cancer participated in a pilot chemoprevention trial and were given 60 mg raloxifene daily for 24 months. Fasting serum samples collected at baseline and after 12 months on drug were used to measure circulating prolactin, estradiol, and sex hormone binding globulin (SHBG) levels. RESULTS: Of the 27 subjects who completed 12 months of raloxifene, 23 had paired prolactin samples, and 20 had paired estradiol and SHBG samples. Prolactin levels did not significantly change with raloxifene treatment, but SHBG levels increased (mean change = 7.3 nmol/L; P = 0.0001; 95% confidence interval, 3.9-10.7). Estradiol (mean change = 42 pg/mL; P = 0.048; 95% confidence interval, 1-84 pg/mL) levels were elevated when comparing 15 of the 20 women with paired estradiol measurements who also had both of these samples taken during the early follicular phase of the menstrual cycle. CONCLUSIONS: This report is the first to examine the long-term effects of raloxifene on prolactin, estradiol, and SHBG levels in premenopausal women who are also at increased risk for developing invasive breast cancer. Raloxifene had no significant effect on prolactin levels but did increase estradiol and SHBG measurements.     

Insulin-Lowering Effects of Metformin in Women with Early Breast Cancer

BackgroundObesity has been associated with poor breast cancer outcomes. Insulin may mediate this effect, interacting with insulin receptors on breast cancer cells. Metformin, a biguanide derivative used in the treatment of diabetes, reduces insulin levels in subjects with type 2 diabetes and other insulin-resistant states. If metformin lowers insulin levels in women with breast cancer, it may also improve breast cancer outcomes.Patients and MethodsWe administered metformin (1500 mg per day) to 32 women with early breast cancer whose baseline insulin levels were at least 45 pmol/L to determine its effect on insulin levels.ResultsTwenty-two (69%) women completed the 6-month intervention. Four women (12.5%) dropped out because of gastrointestinal side effects; the others withdrew for reasons not related to toxicity. Completers were similar to noncompleters for all baseline characteristics apart from global health, overall physical condition, overall quality of life, physical function, and social function (HRQOL), which was decreased in noncompleters. Metformin significantly lowered fasting insulin levels by 15.8 pmol/L (22.4%; P = .024) and improved insulin sensitivity by 25.6% (P = .018), total cholesterol by 5.3%, and low-density lipoprotein (LDL) cholesterol by 9.1%. Metformin reduced weight by 1.9 kg (2.5%; P = .01), and it had no significant effects on HRQOL or specific gastrointestinal symptoms (appetite, nausea/vomiting, diarrhea, constipation).ConclusionMetformin significantly lowers insulin levels, and it improves insulin resistance in nondiabetic women with breast cancer. A phase III randomized trial to evaluate its effects on breast cancer outcomes is recommended.     

Serum C-peptide levels and breast cancer risk: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)

It has been hypothesized that chronic hyperinsulinemia, a major metabolic consequence of physical inactivity and excess weight, might increase breast cancer risk by direct effects on breast tissue or indirectly by increasing bioavailable levels of testosterone and estradiol. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), we measured serum levels of C-peptide--a marker for pancreatic insulin secretion--in a total of 1,141 incident cases of breast cancer and 2,204 matched control subjects. Additional measurements were made of serum sex hormone binding globulin (SHBG) and sex steroids. Conditional logistic regression models were used to estimate breast cancer risk for different levels of C-peptide. C-peptide was inversely correlated with SHBG and hence directly correlated with free testosterone among both pre and postmenopausal women. C-peptide and free estradiol also correlated positively, but only among postmenopausal women. Elevated serum C-peptide levels were associated with a nonsignificant reduced risk of breast cancer diagnosed up to the age of 50 years [odds ratio (OR)=0.70, (95% confidence interval (CI), 0.39-1.24); ptrend=0.05]. By contrast, higher levels of C-peptide were associated with an increase of breast cancer risk among women above 60 years of age, however only among those women who had provided a blood sample under nonfasting conditions [OR=2.03, (95% CI, 1.20-3.43); ptrend=0.01]. Our results do not support the hypothesis that chronic hyperinsulinemia generally increases breast cancer risk, independently of age. Nevertheless, among older, postmenopausal women, hyperinsulinemia might contribute to increasing breast cancer risk.     

Relationship between caffeine intake and plasma sex hormone concentrations in premenopausal and postmenopausal women

BACKGROUND:

Circulating estrogens and androgens are important factors in the development of various female cancers. Caffeine intake may decrease risk of breast and ovarian cancer, although the data are not entirely consistent. Whether or not caffeine affects cancer risk by altering sex hormone levels is currently unknown.

METHODS:

We examined the relationship of caffeine, coffee, decaffeinated coffee, and tea with plasma concentrations of estrogens, androgens, progesterone, prolactin, and sex hormone–binding globulin (SHBG) in 524 premenopausal and 713 postmenopausal women from the Nurses' Health Study (NHS) and NHSII.

RESULTS:

In premenopausal women, caffeine intake was inversely associated with luteal total and free estradiol, and positively associated with luteal progesterone levels (P‐trend = .02, .01, .03, respectively). Coffee intake was significantly associated with lower luteal total and free estradiol levels, but not luteal progesterone levels (P‐trend = .007, .004, .20, respectively). Among the postmenopausal women, there was a positive association between caffeine and coffee intake and SHBG levels (P‐trend = .03 and .06, respectively). No significant associations were detected with the other hormones.

CONCLUSIONS:

Data from this cross‐sectional study suggest that caffeine may alter circulating levels of luteal estrogens and SHBG, representing possible mechanisms by which coffee or caffeine may be associated with pre‐ and postmenopausal malignancies, respectively. Future studies evaluating how caffeine‐mediated alterations in sex hormones and binding protein levels affect the risk of female cancers are warranted. Cancer 2009. © 2009 American Cancer Society.     

Effects of a high-fiber, low-fat diet intervention on serum concentrations of reproductive steroid hormones in women with a history of breast cancer.

PURPOSE: Diet intervention trials are testing whether postdiagnosis dietary modification can influence breast cancer recurrence and survival. One possible mechanism is an effect on reproductive steroid hormones. Participants and METHODS: Serum reproductive steroid hormones were measured at enrollment and 1 year in 291 women with a history of breast cancer who were enrolled onto a randomized, controlled diet intervention trial. Dietary goals for the intervention group were increased fiber, vegetable, and fruit intakes and reduced fat intake. Estradiol, bioavailable estradiol, estrone, estrone sulfate, androstenedione, testosterone, dehydroepiandrosterone sulfate, follicle-stimulating hormone, and sex hormone-binding globulin were measured. RESULTS: The intervention (but not the comparison) group reported a significantly lower intake of energy from fat (21% v 28%), and higher intake of fiber (29 g/d v 22 g/d), at 1-year follow-up (P <.001). Significant weight loss did not occur in either group. A significant difference in the change in bioavailable estradiol concentration from baseline to 1 year in the intervention (-13 pmol/L) versus the comparison (+3 pmol/L) group was observed (P <.05). Change in fiber (but not fat) intake was significantly and independently related to change in serum bioavailable estradiol (P <.01) and total estradiol (P <.05) concentrations. CONCLUSION: Results from this study indicate that a high-fiber, low-fat diet intervention is associated with reduced serum bioavailable estradiol concentration in women diagnosed with breast cancer, the majority of whom did not exhibit weight loss. Increased fiber intake was independently related to the reduction in serum estradiol concentration.     

The Effect of Weight Change During Treatment With Targeted Therapy in Patients With Metastatic Renal Cell Carcinoma

BackgroundThe relationship between weight change during treatment and survival remains poorly characterized in patients with metastatic renal cell carcinoma (mRCC).Patients and MethodsIn this retrospective analysis we included 3311 patients with mRCC treated in phase II/III first-line or second-line targeted therapy clinical trials and assessed the effect of weight change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) at 6 and 12 weeks from treatment initiation. Weight change was defined as weight loss (≥5% reduction), weight gain (≥2% increase), or stable weight from baseline. Survival analyses were performed using the Kaplan–Meier method and adjusted for known prognostic factors using Cox regression multivariable analysis.ResultsOverall, 1916 (58%) had stable weight, 936 (28%) had weight loss, and 459 (14%) had weight gain at 12 weeks. Patients with weight loss at 12 weeks had inferior OS compared with those with stable weight (hazard ratio [HR], 1.494; 95% confidence interval [CI], 1.322-1.688; P < .0001; median OS 18.7 vs. 26.9 months), and shorter PFS (HR, 1.315; 95% CI, 1.189-1.455; P < .0001; median PFS, 7.2 vs. 10.1 months). The ORRs for patients with weight loss, stable weight, and weight gain at 12 weeks were 23.4% (n = 219/936), 32.1% (n = 615/1916), and 35.9% (n = 165/459), respectively (adjusted odds ratio, 0.715; P = .03). Findings were consistent at 6 weeks. Adverse events were similar between groups.ConclusionWe showed that mRCC patients who experience weight loss during treatment have worse outcomes compared with patients with stable weight at 6 and 12 weeks of treatment. Weight loss at 6 weeks from treatment initiation might be an early clinical biomarker of worse survival and might provide prognostic utility.     

Relations of insulin resistance and serum concentrations of estradiol and sex hormone-binding globulin to potential breast cancer risk factors.

There is a hypothesis that hyperinsulinemia or insulin resistance may be a mediator for breast cancer risk factors. On the other hand, some, but not all, of the well-known risk factors of breast cancer have been associated with serum estrogen concentrations. We assessed the relationships of potential breast cancer risk factors to indicators of insulin resistance, fasting plasma insulin concentration and homeostasis model assessment insulin resistance (HOMA-R), in 88 postmenopausal Japanese women. We also examined whether insulin resistance would explain the association of breast cancer risk factors with serum estradiol and sex hormone-binding globulin (SHBG). Information on potential breast cancer risk factors, such as demographic characteristics, smoking and drinking habits, diet, exercise, menstrual and reproductive factors, was obtained by self-administered health questionnaire including a validated semiquantitative food frequency questionnaire. Body mass index (BMI) was significantly correlated with the ratio of estradiol to SHBG (Spearman r = 0.30, P = 0.0004), fasting plasma insulin (r = 0.45) and HOMA-R (r = 0.43, P = 0.0001) after controlling for age. The correlations were still significant between BMI and estradiol / SHBG ratio (r = 0.21, P = 0.047) after controlling for fasting plasma insulin and between BMI and fasting plasma insulin (r = 0.40, P = 0. 0001) as well as HOMA-R (r = 0.38, P = 0.0003) after controlling for estradiol / SHBG ratio. There is a possibility that effect of BMI on breast cancer risk is mediated by both insulin resistance and estrogen metabolism.