The Effect of Overweight and Nutrition on Prognosis in Breast Cancer

In Germany, breast cancer is the most common cancer in women. Its annual incidence is around 58 000 new cases; 17 000 women die due to the cancer every year (1). The five-year survival rate is currently reported to be 83% to 87%. At the end of 2006, an estimated 242 000 women in Germany were living with a breast cancer diagnosis that they had received up to five years previously (1). The women's survival is vastly determined by tumor stage at diagnosis; women with early, non-metastasized tumors can be expected to have a good prognosis. In this sense, breast cancer is more and more assuming the characteristics of a chronic disease.

A report published in 2007 by the World Cancer Research Fund (WCRF) looked into the importance of body weight, nutrition, and physical activity in the development of tumor disease and which recommendations can be deduced from the findings in terms of primary prevention (2). This report and other publications raised a great deal of interest among physicians and cancer patients about the importance of lifestyle for the prognosis of breast cancer.

This review article aims to collect and critically evaluate current study results of the importance of body weight, weight gain, and nutrition for the prognosis of breast cancer, on the basis of a selective literature search.

Methods

After the search terms were defined and agreed, we conducted a PubMed search for the time period from 1966 to June 2010. The search terms we applied were “overweight AND breast cancer prognosis” and “overweight AND breast cancer survival”. Similarly we combined the terms “obesity”, “weight gain”, “diet”, “dietary factors”, “micronutrients”, “vitamins”, “soy”, “green tea”, “selenium”, “antioxidants” with “breast cancer survival” or “prognosis”.

We included in the evaluation only prospective cohort studies and interventional studies, which we selected firstly on the basis of their abstract and then analyzed in total. Smaller cohort studies with fewer than 200 participants were excluded. We included systematic reviews and meta-analyses. Further studies and information were found in the reference lists of the identified studies.

The defined end points were tumor recurrence, breast cancer specific mortality, and all-cause mortality. We evaluated the studies in the basis of the methods used by the World Cancer Research Fund (2). The evidence levels we used were “convincing”, “probable”, “possible”, and “limited”. We regarded recommendations for lifestyle changes as sufficiently sound only on the basis of convincing or probable evidence (2).

We did not conduct a systematic meta-analysis of comparable study data. Instead we adopted weighted hazard ratios (HR) from recently published meta-analyses (3, 4), in order to show effect sizes of individual factors. We used only HR and relative risk (RR) values after multivariate adjustment, in as far as this had been done in the publications we studied, since observational studies regarding diet/nutrition always have a complex association with people’s general health behaviors. It is easy to imagine that a healthy diet is associated with a generally healthy lifestyle, so that studies that investigate the effects of healthy nutrition may attribute successes to this factor when in actual fact the entire lifestyle is responsible.

Results

Association of body weight and prognosis of breast cancer

Even earlier meta-analyses found that obese women have a higher risk for tumor recurrence and a higher mortality compared with slender people (5). Our own research into this topic identified 17 cohort studies (e1–e17). In 13 out of 15 studies with the end point all-cause mortality, a significant positive association between body mass index (BMI) and mortality was found; in one study a trend in this direction was identified (eTable gif ppt). Six out of 12 studies with the end point breast cancer specific mortality showed a significant positive association, three further studies showed a trend, and three studies (e3, e4, e13) did not find any association (eTable).

Premenopausal overweight is associated with a lower risk for developing breast cancer, according to the WCRF data (2), whereas the present study found a positive association between BMI at the time of diagnosis and mortality not only in women with postmenopausal breast cancer but also in those with premenopausal breast cancer. Seven out of nine studies that differentiated between premenopausal and postmenopausal breast cancer showed significant positive associations, one study merely a trend, and one study no association (e4) (eTable). This represents convincing evidence for an association between obesity and all-cause mortality and a probable evidence for an association between obesity and breast cancer specific mortality.

The results were less clear-cut for recurrence rates. Two (e6, e16) out of six studies with the end point breast cancer recurrence showed a significant association with BMI and two further studies (e10, e12) showed a trend; two further studies did not find any association (eTable). An unequivocal conclusion is therefore not possible.

Association of weight gain and breast cancer prognosis

The WCRF report stated that weight gain per se was a risk factor for developing postmenopausal breast cancer (2). Most observational studies found a weight gain in women after a breast cancer diagnosis. Seven cohort studies were identified to determine the importance of weight gain for breast cancer prognosis (e5, e8, e10, e14, e16, e18, e19). Five of six studies with the endpoint all-cause mortality and all four studies with the endpoint breast cancer specific mortality found a significant positive association with weight gain (Table 1 gif ppt). No clear result was found for the end point recurrence rate. Only two of five studies showed a significant positive association with weight gain; three studies showed no association. The results provide convincing evidence of an increase in all-cause mortality and breast cancer specific mortality after weight gain subsequent to a breast cancer diagnosis.

The influence of diet/nutrition on the prognosis
of breast cancer

Only very few cohort studies have thus far investigated the influence of diet/nutrition on the prognosis of breast cancer (6–9, e9, e11, e13, e20–e26). In 11 of these studies, the importance of the composition of macronutrients for mortality was analyzed as an end point.

Only one of three studies providing data about carbohydrate consumption (6, 7, e23) showed a protective effect for a high consumption. Of the six studies including data on fat intake, four showed a trend for a risk increase (7, e20, e21, e23) for a high consumption, only one showed a significantly increased risk (7). Three out of four cohort studies showed a protective effect for dietary fiber (6, 7, e21, e23), in two of these the results reached significance, yielding a pooled hazard ratio of 0.63 (3). A diet rich in fruit, vegetables, wholegrain products, legumes, fowl, and fish also showed a beneficial effect on all-cause mortality (e24, e26). By contrast, a typical Western diet with a high intake of bleached flour products, red meat, full-fat dairy products, etc, was found to be non-beneficial and was associated with an increase in non-breast cancer specific mortality (e24, e26) and a significant increase in all-cause mortality (e26).

Special food products, such as soy products or green tea—An evaluation of the Shanghai Breast Cancer Survival Study (SBCCS) found an inverse relation between the intake of soy products and the risk of recurrence (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.54 to 0.87, highest versus lowest quartile) and all-cause mortality (HR 0.71; CI 0.54 to 0.92) (8). A recent meta-analysis identified three further studies into the topic but did not find this inverse correlation (9).

Only a small number of observational studies and case-control studies have investigated the effect of green tea on breast cancer. A study from Japan, which included 472 patients with breast cancer of stages I–III reported a relative risk for tumor recurrence of 0.56 (CI 0.35 to 0.91), which was found only for women in tumor stages I–II who consumed five or more cups of green tea per day (10). Another cohort study (11) showed a similarly beneficial effect, which was seen upwards from three cups per day. Two formal meta-analyses concluded that the recurrence rate in women with breast cancer of stages I and II could be lowered on the basis of possible evidence (e27, e28). A recommendation for the consumption of green tea or isolated ingredients such as EGCG (epigallocatechin gallate) cannot be concluded from this.

Micronutrients and supplements—Some cohort studies investigated the influence of micronutrients on the prognosis of breast cancer. Individual evaluations have described beneficial effects for calcium (6), vitamin D (6, 12), vitamin B₂, folic acid (7), phosphorus (6), beta carotene, and vitamin C if ingested in food but not if taken as supplements (6, 7, 13, e20). The vast majority of these studies did not find any beneficial effects on the mortality of women with breast cancer for taking individual micronutrients or combinations thereof, such as calcium, folic acid, iron, selenium, zinc, niacin, beta carotene, vitamin A, vitamin C, or vitamin E (3).

Alcohol—Convincing evidence shows that regular consumption of alcohol increases the risk of breast cancer in premenopausal as well as postmenopausal women (2). Our evaluation of the six available cohort studies of women with diagnosed breast cancer presented a different, if not consistent, picture (Table 2 gif ppt). For the end point all-cause mortality, three of the six studies (6, e19, e23, e29–e31) showed no association; three studies reported a drop in all-cause mortality, which is probably due to the known beneficial effect of moderate amounts of alcohol on cardiovascular mortality (e9, e29, e31).

Interventional studies—Two large lifestyle interventional studies in women with early stages of breast cancer have been conducted to date. Both were started in the early 1990s and captured hard end points such as disease-free survival (tumor recurrence, disease-specific mortality, and all-cause mortality). The Women’s Intervention Nutrition Study (WINS) included 975 women who participated in telephone-based lifestyle advice, which aimed primarily to reduce fat intake to less than 15% of the total daily energy intake (14). The therapeutic goal of the Women’s Healthy Eating and Living Study (WHEL) was a reduction in fat intake to 15% to 20% of total energy intake and an increase in the intake of fruits, vegetables, and other foods that are rich in dietary fiber (15).

Neither study found an effect of the intervention on mortality (WINS: HR 0.89; p = 0.56; WHEL: HR 0.97, p = 0.82). The primary end point—recurrence-free survival—was only just missed in the WIN study (HR 0.76, p = 0.077), and clearly missed in the WHEL study (HR 0.99, p = 0.87). A later evaluation of the WHEL study did, however, find a significant interventional effect in women with the best diet (the highest intake of fruits, vegetables, dietary fiber, and lowest amount of fat) (e32).

Discussion

The incidence of breast cancer is increasing in Germany in the same way as in the rest of the world. In view of this increase, new concepts and strategies are desirable to prevent tumor recurrence and improve the quality of life and survival expectancy in those affected. The study results we presented imply that lifestyle choices can modify the prognosis for these patients, but our understanding of these associations is limited and incomplete.

What is currently known is derived almost entirely from cohort studies. Although the cohort sizes have notably increased in recent years and the quality of data collection has improved, intrinsic methodological limitations remain that restrict the validity of the results thus gained. Cohort studies can merely highlight associations; they cannot provide any information on cause and effect. Owing to the multitude of interactions between known and unknown factors—especially in the context of lifestyle—biases and incidental findings cannot be excluded. The result: reliable conclusions are possible only for effects that consistently occur in different cohorts or that have been confirmed in interventional studies.

According to the WCRF’s assessment criteria, the present analysis provides convincing evidence that a high BMI is associated with a worse prognosis for women with breast cancer. This association has a high biological plausibility, as has been shown repeatedly in the recent past (16, 17). A new meta-analysis found an increase in all-cause mortality and breast cancer specific mortality in association with obesity of 30%, respectively, which was more pronounced in premenopausal women than in postmenopausal women (4).

Weight gain after a diagnosis of breast cancer is common (18, 19). The reasons are complex and poorly understood (5, 18, 20, e33, e34). Such weight gain obviously increases the mortality risk, so that this aspect should be subject to great attention in the future.

A result in the present analysis that is particularly worth mentioning is the absence of evidence for the benefit of many products that women with breast cancer are often offered as support measures. This is particularly the case for the multitude of vitamin and mineral preparations on offer. According to a recent US study, more than 60% of women receiving adjuvant therapy for breast cancer take preparations containing beta carotene, vitamin C, vitamin E, or selenium (e35). For individual substances—for example, antioxidant preparations—if taken while undergoing chemotherapy or radiotherapy, a certain risk increase cannot be excluded (21).

An interesting finding of our literature search was the fact that the analysis of the prognostic factors for breast cancer deviates partly from the results reported by the WCFR (2). The WCRF reported convincing evidence for alcohol in the sense of a risk increase for premenopausal and postmenopausal breast cancer, whereas our evaluation did not find a negative influence, however, this is probably masked by the beneficial effects of moderate alcohol consumption on cardiovascular risk. A convincing explanation for this discrepancy is so far lacking.

The two interventional studies in women with breast cancer that have been conducted so far (14, 15) addressed the question of the degree to which reducing fat intake to below 15% to 20% of the total energy intake improves the prognosis. The intervention programs did, however, not consider the quality of the fat and left body weight and exercise activity altogether out of the analysis. Since the desired fat reduction was only partly successful and had little effect on prognosis, the question is how future lifestyle intervention programs for women with breast cancer should be designed. Subgroup analyses of both studies showed that if the instructions were adhered to then a positive influence on individual end variables was noted (e32). However, nowadays the consensus is mostly that the focus is on weight management and exercise and that multimodal approaches should be studied (22).

On this background, new interventional studies are urgently needed. In view of the good prognosis for women with non-metastatic breast cancer (1), other intervention objectives should also be considered, such as the reduction of cardiovascular disorders that is to be expected from life style adjustment, as well as type 2 diabetes or the women’s quality of life. Lifestyle programs should not be limited only to preventing tumor recurrence, as their benefits can be assumed to be rather more comprehensive. In Germany, the SUCCESS-C Study is currently investigating the benefit of a two-year lifestyle intervention with moderate weight reduction on the recurrence-free survival of women with non-metastatic breast cancer (23).

Conflict of interest statement

Professor Janni has received unrestricted educational grants from Sanofi-Aventis, Chugai, and Pfizer.

Dr Rack has been reimbursed for participation fees for continuing medical educational events and travel expenses by Sanofi-Aventis, Amgen, Pfizer, AstraZeneca, Chugai, Novartis, and Cephalon. She has received honoraria for presenting from Sanofi-Aventis, Amgen, Pfizer, Novartis, Chugai, and Lilly.

Professor H Hauner has in the past received honoraria for presenting from Sanofi-Aventis, Lilly, Novartis, NovoNordisk, Abbott, and BMS. Furthermore he has received honoraria for acting as an adviser from Nycomed and WeightWatchers, and is currently the principal investigator in a drug trial conducted by Riemser.

Dr D Hauner declares that no conflict of interest exists.

Manuscript received on 17 August 2010, revised version accepted on
9 May 2011.

Translated from the original German by Dr Birte Twisselmann.

Corresponding author
Prof. Dr. med. Hans Hauner
Else Kröner-Fresenius-Zentrum für Ernährungsmedizin
Klinikum rechts der Isar der Technischen Universität München
Ismaninger Str. 22
81675 München, Germany
hauner@wzw.tum.de

@For eReferences please refer to:
www.aerzteblatt-international.de/ref4711

eTable:
www.aerzteblatt-international.de/11m0795