Purpose: Randomized clinical trials (RCT) are inconclusive regarding the role of dietary interventions in anthropometric measurements and survival in breast cancer patients. Our aim was to conduct a systematic review and meta-analysis to assess the effects of diet on these outcomes in women treated for early-stage breast cancer. Methods: Embase, MEDLINE, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched for RCT comparing dietary interventions (individualized dietary counseling, prescription of a specific diet, or others) with usual care in women that were treated for early breast cancer. Primary outcomes were overall survival (OS) and disease-free survival (DFS); secondary outcome was a change in body mass index (BMI). Results: We found 12 RCT eligible for analysis, 7 of which were included in the quantitative analysis. Two studies reported OS and DFS and 6 reported BMI data. The hazard ratio (HR) for OS and DFS was 0.91 (95% confidence interval [CI] 0.77–1.07, p = 0.25) and 0.92 (95% CI 0.79–1.08, p = 0.31) for the intervention and control groups, respectively. Intervention was associated with BMI reduction in subjects who received a specific diet instead of counseling or other types of intervention (–0.67; 95% CI –1.14 to –0.21). Conclusions: Despite increasing survival among breast cancer patients due to better oncological treatments, there is still a lack of prospective data regarding the effects of dietary interventions in this population. We found positive association between prescription of specific diets in terms of anthropometric measures; there were no differences in OS or DFS.

Breast cancer is the major cancer among women worldwide and the leading cause of death in many countries [1, 2]. Despite advances in medical, surgical, and radiation treatments as well as in screening methods, around 30% of all initial breast cancer cases will recur.

Approximately half of breast cancer patients in Western countries are overweight or obese at the time of diagnosis [3]. Moreover, up to 60% of women will gain weight during oncological treatment [4]. Obesity and weight gain after the diagnosis are related to poor overall survival (OS) and disease-free survival (DFS) [5, 6]. Physical activity and dietary interventions limit weight gain among breast cancer patients [7], which can improve outcomes and contribute to reducing breast cancer-specific mortality, according to observational studies [8]. There is 1 clinical trial that assessed physical interventions and mortality in early breast cancer showing better OS and DFS with the interventions [9, 10].

Observational studies show that the quality of the diet could reduce the risk of breast cancer recurrence, but none assessed the risk of death [11, 12]. There are scant data about dietary interventions and their relationship with outcomes in early breast cancer patients.

We aimed to conduct a systematic review and meta-analysis to assess the effects of dietary interventions in anthropometric measures and survival in women after the treatment of early breast cancer.

Protocol

The protocol of this systematic review and meta-analysis was published previously [13] (PROSPERO registry CRD42014008743). The systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions (CHSRI) [14] and the data reported according to PRISMA recommendations [15].

Data Sources

The electronic databases Embase, MEDLINE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials were consulted for indexed literature including papers, abstracts, or reports up to May 2020 (online suppl. Material; see www.karger.com/doi/10.1159/000514469 for all online suppl. material, Search Strategy). We also searched in the grey literature in the annals of meetings and ongoing trials at ClinicalTrials.gov.

Study Selection

We included randomized clinical trials (RCT) that evaluated the effects of dietary interventions (individualized dietary counseling, prescription of a specific diet, or others) compared to usual care in women who received treatment for stage I–III breast cancers. We excluded studies that applied the intervention after 5 years from diagnosis and also studies whose patients were on chemotherapy and/or radiation therapy; hormone therapy was allowed.

The primary outcomes were OS and DFS (5 years after treatment or until the maximum follow-up period). The secondary endpoint was body mass index (BMI). Other endpoints included in the protocol report [13] were waist-to-hip ratio (WHR), estradiol levels, insulin levels, testosterone levels, SHBG levels, and quality of life; these variables were reported for the qualitative analysis.

The evaluation of titles and abstracts and the inclusion of papers and data extraction were conducted by HAVT, FSF, FKA, and MRRF in pairs, independently, and using a standardized form. All disagreements were solved through discussion with the senior author.

Data Extraction

The data used for the meta-analysis and comparison between usual care and the intervention were the same as in our previous study [10]. Briefly, for the primary outcomes OS and DFS, we used hazard ratios (HRs) with 95% confidence intervals (CIs). OS was defined as the interval between randomization and death for any cause or censoring of data; DFS was defined as the interval between the randomization and any breast cancer-related event including death, or censoring data. For continuous outcomes, we used the final values of both groups after the intervention, since these were the data most frequently found, to minimize the need for imputations. Studies without both initial and final values were excluded from the analysis. For studies that presented only values of the difference between final results and initial results, the final values were calculated from a simple sum of the variation with the initial value. In this case, the standard deviation (SD) values used were the same as the initial values of the variables. Some final SD values were not reported, e.g., in Parekh et al. [16] and Ramirez et al. [17]; in this event, we used the initial SD. For the study of Chlebowski et al. [18], we used the imputation formula, based on the CI, to obtain the final SD. The studies of Holm et al. [19], Chlebowski et al. [20] and Zuniga et al. [21] were excluded from the meta-analysis due the lack of data for analysis or imputations, and that of Thomson et al. [22] was excluded since it described a population that was likely already described by Rock et al. [23].

Quality Assessment

The quality evaluation of all studies was carried out in the same way as for study selection and data extraction, always paired and in accordance with the CHSRI [14] through the Cochrane risk-of-bias tool. The overall quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) [24], and was classified as “high,” “moderate,” “low,” or “very low.”

Data Synthesis and Analysis

The data were combined using the random-effects meta-analysis model, with the DerSimonian-Laird estimator as a variance estimator, and the treatment effect was estimated using the mean difference (MD) as a summary measure for continuous outcomes. All analyses were performed using R v3.2.1, meta packages v4.9–2. Statistical heterogeneity was assessed in each meta-analysis using the statistic I2, and heterogeneity was considered substantial if I2 was >50%. Publication bias was assessed using a funnel-plot, and its effect on the interpretation of the results was evaluated by a trim-and-fill computation.

Literature Search

A total of 23,249 records were identified in the database search. There were 4,308 duplicated records, leaving 18,941 for title and abstract analysis; 18,863 records were excluded, leaving 78 studies for full-text analysis. After that, 12 studies provided data for the qualitative analysis [16-23, 25-28], 7 of which were included in the meta-analysis. The flowchart of the search is presented in Figure 1. Study characteristics are presented in Table 1. The risk of bias in the studies is summarized in Figure 2 (also in online suppl. Fig. 3).

Table 1.

Characteristics of the studies

Characteristics of the studies
Characteristics of the studies
Fig. 1.

PRISMA flow chart. Created by Review Manager 5.3.

Fig. 1.

PRISMA flow chart. Created by Review Manager 5.3.

Close modal
Fig. 2.

Risk of bias summary. Created by Review Manager 5.3.

Fig. 2.

Risk of bias summary. Created by Review Manager 5.3.

Close modal

Study Characteristics

A total of 6,087 patients were allocated in 7 studies. The mean duration of interventions was 15.7 months (range 2–60 months). The maximum follow-up period was 108 months and the minimum was 2 months. Two studies reported OS and DFS data, i.e., the WINS [27] and WHEL [26] trials with 108 and 87.6 months of follow-up, respectively.

Outcomes

Regarding the primary outcomes, the interventions did not promote a significant mortality reduction in all subset of patients (HR 0.91; 95% CI 0.77–1.07, p = 0.25, I2 = 7%, low-quality evidence) (Fig. 3). Similarly, there was no improvement in DFS in the intervention group (HR 0.92; 95% CI 0.79–1.08, p = 0.31, I2 = 52%, very low-quality evidence) (Fig. 4). Due to a trend of better DFS for ER-negative and PR-negative patients allocated in the intervention group in WINS, we performed a subgroup analysis, stratifying participants with hormone receptor-positive and hormone receptor-negative tumors. This analysis showed no benefits of dietary interventions in DFS (HR 0.87; 95% CI 0.68–1.1, p = 0.23, I2 = 62%, high-quality evidence) (Fig. 4).

Fig. 3.

Forest plot for overall survival. Created by RStudio v1.1.453.

Fig. 3.

Forest plot for overall survival. Created by RStudio v1.1.453.

Close modal
Fig. 4.

Forest plot for DFS sorted by hormonal receptor status (ER-positive and/or PR-positive vs. hormone receptor-negative). Created by RStudio v1.1.453.

Fig. 4.

Forest plot for DFS sorted by hormonal receptor status (ER-positive and/or PR-positive vs. hormone receptor-negative). Created by RStudio v1.1.453.

Close modal

General dietary interventions were not associated with a reduced BMI (–0.32; 95% CI –0.95 to 0.30, p = 0.31, I2 = 21%, very-low quality evidence), but there was a significant reduction (–0.67; 95% CI –1.14 to –0.21, very low-quality evidence) (Fig. 5) in subjects who received a specific diet instead of counseling or other types of intervention.

Fig. 5.

Forest plot for BMI reduction sorted by type of intervention. Created by RStudio v1.1.453.

Fig. 5.

Forest plot for BMI reduction sorted by type of intervention. Created by RStudio v1.1.453.

Close modal

The Egger test for asymmetry and publication bias was not conducted since there were <10 trials. Visual asymmetry was used as described by Sterne et al. [29, 30]. Since there were only a few outcomes, trim-and-fill analysis was performed for all outcomes and there was no loss of significance after that (online suppl. Fig. 1, 2).

This study is the first meta-analysis of RCT that reported data on OS and DFS of dietary interventions exclusively, without combining physical activity and other interventions. Other meta-analyses assessed the same outcomes but included observational studies [6]. Our goal was to collect the best evidence available; we therefore chose to include only RCT comparing the impact of dietary interventions against usual care.

Our meta-analysis provides data on the OS and DFS of 5,525 patients from the WINS [27] and WHEL [26] trials. There were no differences in outcomes compared to usual care with regard to OS or DFS, even when stratifying by hormonal receptor status. DFS was better for patients allocated to the intervention group in WINS, mainly for those with ER-/PR-negative tumors, but this difference was not shown in the WHEL trial. There are some aspects of these studies to point out. First, in WINS there was a difference in BMI favoring the intervention group, which could explain better relapse-free survival and the trend for a better OS. In WHEL, there were no differences between groups in terms of BMI, either at baseline or the end of the study. Second, WINS reported a high rate of missing dietary intake data at the 5-year assessment, i.e., for only 39% of the intervention group and 44% of the control group. Third, the subjects were different in the 2 studies. WINS had more patients with stage I disease (54 vs. 38%) and less stage II and III patients (42 vs. 57% and 3.5 vs. 5%, respectively). WHEL did not include patients with tumors <1 cm or patients aged >70 years at randomization. Moreover, treatment regimens, age, and prognostic factors were different in the 2 trials.

We found a slight difference in terms of BMI reduction favoring the group whose intervention was the prescription of a specific diet. The interventions in all 5 studies, including WINS and WHEL, did not aim to reduce weight by means of a hypocaloric diet. Only in WINS there was a reduction in BMI in the intervention arm, mainly due to significantly less fat intake (–8%) than in the control arm.

Recently, Chlebowski et al. [31] published an update of the Women’s Health Initiative (WHI) Dietary Modification which randomized 48,835 postmenopausal women with no prior breast cancer to receive a 8.5-year low-fat diet or usual diet intervention. After 19.6 years of follow-up, there was a nonsignificant difference in new cases of breast cancer that favored the intervention group (HR 0.95, 95% CI 0.89–1.02), but fewer deaths related to breast cancer (HR 0.85, 95% CI 0.74–0.96). Despite not being the same population as in our meta-analysis, this result sheds light on the importance of recommending high-quality diets for all postmenopausal women with breast cancer.

Our meta-analysis has several limitations. First, there was a lack of good-quality data on anthropometric measures accordingly to GRADE quality assessment (very low-quality evidence; Table 2). Second, some of the studies did not report the pathologic features of tumors, such as hormone receptor and HER2 status. Third, 2 studies [17, 21] included only overweight or obese women whereas the great majority of studies included patients in all BMI groups. Finally, the interventions were heterogeneous across studies, in terms of the diet that was prescribed (regarding fat content, caloric intake, etc.), the duration of the intervention, and the way patients were supervised during the study, thus explaining why (in some instances) a significant weight loss was achieved and sometimes it was not. This heterogeneity might explain why a more robust benefit was not seen in this analysis; it makes a point for ongoing investigation for the best dietetic interventions in survivors of breast cancer.

Table 2.

GRADE assessment

GRADE assessment
GRADE assessment

Considering all limitations, our meta-analysis provided data on OS and DFS of early breast cancer survivors who underwent dietetic interventions after completing breast cancer treatment. We found no differences in OS and DFS in the groups, probably because the interventions did not significantly reduce the BMI. Despite the lack of evidence supporting dietary interventions, survivors are oriented to maintain or reduce weight through a high-quality food diet and low caloric intake because this intervention is cheap and has no significant adverse effects. Therefore, interventions targeting weight control and healthier behaviors must be assessed by high-quality evidence studies.

The authors declare there were no conflicts of interest.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

H.A.V.T.: conceptualization, methodology, formal analysis, investigation, data curation, writing (original draft, review, and editing), visualization, and project administration; F.S.F.: conceptualization, methodology, formal analysis, investigation, and writing (review and editing); F.K.A.: conceptualization, methodology, investigation, and writing (review and editing); M.R.R.F.: methodology, formal analysis, and investigation; R.A.R.: conceptualization, methodology, writing (review and editing), and supervision; D.D.R.: conceptualization, methodology, investigation, writing (review and editing, visualization), and supervision.

1.
Bray
F
,
Ferlay
J
,
Soerjomataram
I
,
Siegel
RL
,
Torre
LA
,
Jemal
A
.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
.
CA Cancer J Clin
.
2018
Nov
;
68
(
6
):
394
424
.
[PubMed]
0007-9235
2.
Janni
W
.
Breast Cancer - a Lifestyle Disease?
Breast Care (Basel)
.
2018
Apr
;
13
(
2
):
84
5
.
[PubMed]
1661-3791
3.
Irwin
ML
,
McTiernan
A
,
Baumgartner
RN
,
Baumgartner
KB
,
Bernstein
L
,
Gilliland
FD
, et al
Changes in body fat and weight after a breast cancer diagnosis: influence of demographic, prognostic, and lifestyle factors
.
J Clin Oncol
.
2005
Feb
;
23
(
4
):
774
82
.
[PubMed]
0732-183X
4.
Vance
V
,
Mourtzakis
M
,
McCargar
L
,
Hanning
R
.
Weight gain in breast cancer survivors: prevalence, pattern and health consequences
.
Obes Rev
.
2011
Apr
;
12
(
4
):
282
94
.
[PubMed]
1467-7881
5.
Protani
M
,
Coory
M
,
Martin
JH
.
Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis
.
Breast Cancer Res Treat
.
2010
Oct
;
123
(
3
):
627
35
.
[PubMed]
0167-6806
6.
Chan
DS
,
Vieira
AR
,
Aune
D
,
Bandera
EV
,
Greenwood
DC
,
McTiernan
A
, et al
Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies
.
Ann Oncol
.
2014
Oct
;
25
(
10
):
1901
14
.
[PubMed]
0923-7534
7.
Goodwin
P
,
Esplen
MJ
,
Butler
K
,
Winocur
J
,
Pritchard
K
,
Brazel
S
, et al
Multidisciplinary weight management in locoregional breast cancer: results of a phase II study
.
Breast Cancer Res Treat
.
1998
Mar
;
48
(
1
):
53
64
.
[PubMed]
0167-6806
8.
Holmes
MD
,
Chen
WY
,
Feskanich
D
,
Kroenke
CH
,
Colditz
GA
.
Physical activity and survival after breast cancer diagnosis
.
JAMA
.
2005
May
;
293
(
20
):
2479
86
.
[PubMed]
0098-7484
9.
Hayes
SC
,
Steele
M
,
Spence
R
,
Pyke
C
,
Saunders
C
,
Bashford
J
, et al
Can exercise influence survival following breast cancer: results from a randomised, controlled trial
.
J Clin Oncol
.
2017
;
35
(
15
suppl
):
10067
. 0732-183X
10.
Soares Falcetta
F
,
de Araújo Vianna Träsel
H
,
de Almeida
FK
,
Rangel Ribeiro Falcetta
M
,
Falavigna
M
,
Dornelles Rosa
D
.
Effects of physical exercise after treatment of early breast cancer: systematic review and meta-analysis
.
Breast Cancer Res Treat
.
2018
Aug
;
170
(
3
):
455
76
.
[PubMed]
0167-6806
11.
Zhang
S
,
Folsom
AR
,
Sellers
TA
,
Kushi
LH
,
Potter
JD
.
Better breast cancer survival for postmenopausal women who are less overweight and eat less fat. The Iowa Women’s Health Study
.
Cancer
.
1995
Jul
;
76
(
2
):
275
83
.
[PubMed]
0008-543X
12.
Jain
M
,
Miller
AB
,
To
T
.
Premorbid diet and the prognosis of women with breast cancer
.
J Natl Cancer Inst
.
1994
Sep
;
86
(
18
):
1390
7
.
[PubMed]
0027-8874
13.
Falavigna
M
,
Lima
KM
,
Giacomazzi
J
,
Paskulin
D
,
Hammes
LS
,
Ribeiro
RA
, et al
Effects of lifestyle modification after breast cancer treatment: a systematic review protocol
.
Syst Rev
.
2014
Jul
;
3
(
1
):
72
.
[PubMed]
2046-4053
14.
Higgins
J
,
Green
S
, editors
. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011] [Internet]. The Cochrane Collaboration;
2011
. Available from: http://handbook.cochrane.org
15.
Liberati
A
,
Altman
DG
,
Tetzlaff
J
,
Mulrow
C
,
Gøtzsche
PC
,
Ioannidis
JPA
, et al
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
BMJ.
2009
;339(jul21 1):b2700.
16.
Parekh
N
,
Jiang
J
,
Buchan
M
,
Meyers
M
,
Gibbs
H
,
Krebs
P
.
Nutrition Literacy among Cancer Survivors: Feasibility Results from the Healthy Eating and Living Against Breast Cancer (HEAL-BCa) Study: a Pilot Randomized Controlled Trial
.
J Cancer Educ
.
2018
Dec
;
33
(
6
):
1239
49
.
[PubMed]
0885-8195
17.
Ramirez
AG
,
Muñoz
E
,
Long-Parma
D
,
Mendoza
KD
,
Holden
AEC
,
Wargovich
MJ
. Abstract A66: An anti-inflammatory dietary intervention to reduce breast cancer recurrence risk: Preliminary data from a pilot study. In
2016
.
18.
Chlebowski
RT
,
Blackburn
GL
,
Thomson
CA
,
Nixon
DW
,
Shapiro
A
,
Hoy
MK
, et al
Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study
.
J Natl Cancer Inst
.
2006
Dec
;
98
(
24
):
1767
76
.
[PubMed]
0027-8874
19.
Holm
LE
,
Nordevang
E
,
Ikkala
E
,
Hallström
L
,
Callmer
E
.
Dietary intervention as adjuvant therapy in breast cancer patients—a feasibility study
.
Breast Cancer Res Treat
.
1990
Sep
;
16
(
2
):
103
9
.
[PubMed]
0167-6806
20.
Chlebowski
RT
,
Nixon
DW
,
Blackburn
GL
,
Jochimsen
P
,
Scanlon
EF
,
Insull
W
 Jr
, et al
A breast cancer Nutrition Adjuvant Study (NAS): protocol design and initial patient adherence
.
Breast Cancer Res Treat
.
1987
Oct
;
10
(
1
):
21
9
.
[PubMed]
0167-6806
21.
Zuniga
KE
,
Parma
DL
,
Muñoz
E
,
Spaniol
M
,
Wargovich
M
,
Ramirez
AG
.
Dietary intervention among breast cancer survivors increased adherence to a Mediterranean-style, anti-inflammatory dietary pattern: the Rx for Better Breast Health Randomized Controlled Trial
.
Breast Cancer Res Treat
.
2019
Jan
;
173
(
1
):
145
54
.
[PubMed]
0167-6806
22.
Thomson
CA
,
Rock
CL
,
Giuliano
AR
,
Newton
TR
,
Cui
H
,
Reid
PM
, et al;
Women’s Healthy Eating & Living Study Group
.
Longitudinal changes in body weight and body composition among women previously treated for breast cancer consuming a high-vegetable, fruit and fiber, low-fat diet
.
Eur J Nutr
.
2005
Feb
;
44
(
1
):
18
25
.
[PubMed]
1436-6207
23.
Rock
CL
,
Flatt
SW
,
Thomson
CA
,
Stefanick
ML
,
Newman
VA
,
Jones
LA
, et al
Effects of a high-fiber, low-fat diet intervention on serum concentrations of reproductive steroid hormones in women with a history of breast cancer
.
J Clin Oncol
.
2004
Jun
;
22
(
12
):
2379
87
.
[PubMed]
0732-183X
24.
Balshem
H
,
Helfand
M
,
Schünemann
HJ
,
Oxman
AD
,
Kunz
R
,
Brozek
J
, et al
GRADE guidelines: 3. Rating the quality of evidence
.
J Clin Epidemiol
.
2011
Apr
;
64
(
4
):
401
6
.
[PubMed]
0895-4356
25.
Blackburn
GL
,
Wang
KA
.
Dietary fat reduction and breast cancer outcome: results from the Women’s Intervention Nutrition Study (WINS)
.
Am J Clin Nutr
.
2007
Sep
;
86
(
3
):
s878
81
.
[PubMed]
0002-9165
26.
Pierce
JP
,
Natarajan
L
,
Caan
BJ
,
Parker
BA
,
Greenberg
ER
,
Flatt
SW
, et al
Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: the Women’s Healthy Eating and Living (WHEL) randomized trial
.
JAMA
.
2007
Jul
;
298
(
3
):
289
98
.
[PubMed]
0098-7484
27.
Chlebowski
RT
,
Blackburn
GL
,
Hoy
MK
,
Thomson
CA
,
Giuliano
AE
,
McAndrew
P
, et al
Survival analyses from the Women’s Intervention Nutrition Study (WINS) evaluating dietary fat reduction and breast cancer outcome
.
J Clin Oncol
.
2008
;
26
(
15
suppl
):
522
. 0732-183X
28.
Cho
SW
,
Kim
JH
,
Lee
SM
,
Lee
SM
,
Choi
EJ
,
Jeong
J
, et al
Effect of 8-week nutrition counseling to increase phytochemical rich fruit and vegetable consumption in korean breast cancer patients: a randomized controlled trial
.
Clin Nutr Res
.
2014
Jan
;
3
(
1
):
39
47
.
[PubMed]
2287-3732
29.
Sterne
J
,
Egger
M
,
Smith
D
. Investigating and dealing with publication and other biases. In:
Egger
M
,
Smith
D
,
Altman
D
, editors
.
Systematic revies in health care: meta-analysis in context
.
London
:
BMJ Books
;
2001
.
30.
Sterne
JA
,
Egger
M
.
Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis
.
J Clin Epidemiol
.
2001
Oct
;
54
(
10
):
1046
55
.
[PubMed]
0895-4356
31.
Chlebowski
RT
,
Aragaki
AK
,
Anderson
GL
,
Pan
K
,
Neuhouser
ML
,
Manson
JE
, et al;
Women’s Health Initiative
.
Dietary Modification and Breast Cancer Mortality: Long-Term Follow-Up of the Women’s Health Initiative Randomized Trial
.
J Clin Oncol
.
2020
May
;
38
(
13
):
1419
28
.
[PubMed]
0732-183X
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