Dietary Intake of Omega-3 fatty acids and Endocrine-related Gynecological Cancer: A Meta-Analysis of Observational Studies.

PURPOSE: Previous observational epidemiological studies have reported inconsistent findings on the association between dietary intake of omega-3 fatty acids and endocrine-related gynecological cancer such as ovarian cancer and endometrial cancer. This study aimed to investigate this association using a meta-analysis of observational studies.
MATERIALS AND METHODS: We searched PubMed, EMBASE, and Cochrane library by using key words related with the topic in April 2017. The pooled odd ratios (pORs), relative risks (pRRs), or hazard ratios (pHRs) with 95% confidence intervals (CIs) were calculated based on the random-effects model. Also, we performed subgroup meta-analysis by methodological quality, types of cancer, study design, and omega-3 fatty acids.
RESULTS: A total of ten observational studies with six case-control and four cohort studies were included in the final meta-analysis. In the meta-analysis of all the studies, dietary intake of total omega-3 fatty acids was not significantly associated with the risk of endometrial and ovarian cancers (pOR/HR, 0.87; 95% CI, 0.73-1.04; I2=67.2%) (highest versus lowest intake). In the subgroup meta-analysis by type of study, there was no significant association between them in cohort studies (pHR, 1.03; 95% CI, 0.63-1.67, I2=81.9%), whereas its reduced risk was observed in case-control studies (pOR, 0.81; 95% CI, 0.67 to 0.98, I2=55.7%).
CONCLUSION: The current meta-analysis of observational studies suggests that there is no higher level of evidence to support the protective effect of dietary omega-3 fatty acids on endocrine-related gynecological cancer. Further prospective studies should be conducted to confirm the association.

Introduction

Endometrial cancer and ovarian cancer are the most and second common type of gynecological malignancies, respectively, which are also called endocrine-related gynecological cancers [1]. There are several risk factors for endometrial cancer, which include body mass index, parity, age at menarche, oral contraceptives, diabetes, and smoking [2]. Age, contraceptive use, pregnancy, breastfeeding, and tubal ligation are known to be related to an increased risk of ovarian cancer [2].

In the meantime, it has been reported that biomarkers of inflammation such as C-reactive protein (CRP), interleukin-6, and tumor necrosis factor α are related to the increased risk of endometrial cancer [3,4] and ovarian cancer [5]. Previous meta-analyses of observational epidemiological studies have suggested that regular use of non-steroidal anti-inflammatory drug might be protective against these cancers [6,7]. Further, observational epidemiological studies [8,9] and randomized clinical trials [10-12] reported that omega-3 fatty acids such as α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA), which are polyunsaturated fatty acids abundant in vegetables, fruit, fatty fish, and supplements, might have anti-inflammatory actions. Regarding the potential effects of omega-3 fatty acids on the risk of endocrine-related gynecological cancers, several observational studies such as case-control studies and cohort studies [13-22] have reported inconsistent findings. However, no meta-analysis has been published on this topic.

The current study aimed to investigate the associations between dietary intake of omega-3 fatty acids and endocrine-related gynecological cancers by using a meta-analysis of observational epidemiological studies such as case-control studies and cohort studies and subgroup meta-analyses by various factors such as type of cancer, type of study design, type of omega-3 fatty acids, and study quality.

Materials and Methods

1. Literature search

Three different databases including MEDLINE (PubMed), EMBASE, and the Cochrane Library were systematically searched from their inception to April 2017 by using common keywords related to omega-3 fatty acids and endocrine-related gynecological cancers. The keywords for literature searching were listed as follows: “omega-3 fatty acid,” “fish oil,” “eicosapentaenoic acid,” “alpha-linolenic acid,” “docosahexaenoic acid,” “docosapentaenoic acid” for exposure factors; “endometrial cancer,” “uterine cancer,” and “ovarian cancer” for outcome factors. The bibliographies of relevant studies were also reviewed to identify additional publications. The languages of publication were not limited.

2. Study selection and eligibility criteria

The following are eligibility criteria for individual studies included in the meta-analysis: observational epidemiological studies such as case-control studies and prospective or retrospective cohort studies; studies that investigated the associations between dietary intake of omega-3 fatty acids and the risk of endocrine-related gynecological cancer. For studies using the same data, the more comprehensive study or the first published one was included in the final analysis. Based on the eligibility criteria, two investigators (Tung H and Thu Thi P) independently selected the potential studies.

3. Methodological quality assessment

We assessed the methodological quality of the included studies based on the Newcastle Ottawa Scale for observational studies [23]. The Newcastle Ottawa Scale consists of 3 subscales such as selection of studies, comparability, and exposure. Its star system ranges between 0 and 9. In our study, a study given more than a mean score in each study type was considered as having high quality.

4. Main and subgroup analyses

In the main analysis, we investigated the association between dietary intake of overall omega-3 fatty acids (highest versus lowest intake) and the risk of endocrine-related gynecological cancer. Subgroup meta-analyses were performed by type of study design (case-control study or cohort study), type of cancer (endometrial cancer or ovarian cancer), type of omega-3 fatty acids (ALA, EPA, DHA, or DPA), and methodological quality (high or low).

Bidoli et al. [14] and Tavani et al. [15] used the same dataset and transformed into the consumption of ALA and total omega-3 fatty acids intake in risk of ovarian cancer, respectively. To avoid overlaps, study of Bidoli et al. [14], which omega-3 fatty acids were performed much more specific, was only included in subgroup analysis. Besides, Tavani et al. [15] did not show the result for total omega-3 fatty acids and this study was also assessed for subgroup analysis by type of omega-3 fatty acids only.

5. Statistical analyses

We used adjusted odds ratios, relative risks, or hazard ratios (HRs) with 95% confidence intervals (CIs) from individual studies in order to calculate a pooled effect size. To measure heterogeneity across studies, we used Higgins I2 [24], which is calculated as the following formula:

I2=100%×(Q–df)/Q

, where Q is Cochran’s heterogeneity statistic and df is the degrees of freedom. Negative values of I2 are set at zero; I2 ranges from 0% (no heterogeneity) to 100% (maximal heterogeneity). If I2 value is greater than 50%, it represents the substantial heterogeneity [25]. Because individual studies were conducted in different populations, the random-effects model with the DerSimonian and Laird method was used to calculate the pooled effect size [26,27].

Publication bias was assessed by using the Begg’s funnel plot and Egger’s test [28]. If the funnel plot is asymmetric or the p-value for Egger’s test is lower than 0.05, there exists publication bias. The Stata SE ver. 14.0 software (StataCorp., College Station, TX) was used for all statistical analyses.

Results

1. Selection of relevant studies

Fig. 1 illustrates a flow diagram to identify relevant studies. A total of 3,531 articles were obtained from three databases. Among them, 375 duplicate articles were excluded. After reviewing a title and abstract of each article, we excluded 3,112 articles that did not satisfy selection criteria. Among them, 34 articles were excluded after reviewing the full texts of the remaining 44 articles. The reasons for exclusion were not relevant to study topic (n=9) and insufficient data for study outcome (n=25). A total of 10 studies with six case-control studies [14-17,19,22] and four cohort studies [13,18,20,21] were included in the final analysis.

Fig. 1.

Flow diagram for selection of relevant studies.

2. General characteristics of studies

The general characteristics of the nine studies included in the final analysis are summarized in Table 1. The included studies were five case-control studies with a total of 12,523 participants consisting of 5,279 cases and 7,244 controls, which were published between 2002 and 2014 and four cohort studies with a total of 237,714 participants, which were published between 2002 and 2016. They were conducted in the United States (n=6), Italy (n=2), and Australia (n=1). The follow-up periods ranged between 1980 and 2013.

Table 1.

General characteristics of 10 observational studies included in the analysis

Study	Source of participants (country)	Population (follow-up period)	Cancer type	Type of dietary omega-3 fatty acids	OR or RR or HR (95% CI)	Adjusted variable
Case-control study (n=6)
Bidoli et al. (2002) [14]	Multicentric case-control study (Italy)	1,031 Cases/2,411 controls (1991-1999)	Ovarian cancer	ALA	OR: 0.8 (0.6-1.0)	Age, study center, year of interview, education, parity, oral contraceptive use, and energy intake
Tavani et al. (2003) [15]				Total omega-3 fatty acids	OR: 0.6 (0.4-0.7)	Age, study center, education, body mass index (BMI), energy intake, and parity
Lucenteforte et al. (2008) [16]	Case-control study (Italy)	454 Cases/908 controls (1992-2006)	Endometrial cancer	ALA	OR: 1.0 (0.7-1.6)	Age and study center, adjusted for year of interview, education, physical activity, BMI, history of diabetes, age at menarche, age at menopause, parity, oral contraceptives use, hormone replacement therapy use, and total energy intake
Ibiebele et al. (2012) [17]	Australian ovarian cancer case-control study (Australia)	1,366 Cases/1,414 controls (2002-2005)	Ovarian cancer	ALA	OR: 1.19 (0.93-1.52)	Age, education, BMI, smoking status, oral contraceptive use, parity, menopausal status, hormonal replacement therapy, total fat intake, total energy, and total ω-6 fatty acid intake
				EPA	OR: 0.87 (0.70-1.09)
				DHA	OR: 0.92 (0.74-1.15)
				DPA	OR: 1.06 (0.85-1.33)
				Total omega-3 fatty acids	OR: 1.01 (0.80-1.28)
Arem et al. (2013) [22]	Population-based case-control study (United States)	556 Cases/533 controls (2004-2008)	Endometrial cancer	ALA	OR: 0.91 (0.63-1.32)	Energy consumption, age, BMI, number of live births, menopausal status, oral contraceptive use, hypertension, smoking status, and race/ethnicity
				EPA	OR: 0.57 (0.39-0.84)
				DHA	OR: 0.64 (0.44-0.94)
				Total omega-3 fatty acids	OR: 0.75 (0.52-1.09)
Merritt et al. (2014) [19]	New England case-control study (United States)	1,872 Cases/1,978 controls (1992-2008)	Ovarian cancer	Total omega-3 fatty acids	OR: 0.79 (0.66-0.96)	Age, study center, study phase, number of oral contraceptive use, family history of ovarian cancer, and history of tubal ligation
Cohort study (n=4)
Bertone et al. (2002) [13]	Nurses' Health Study cohort (United States)	80,258 Nurses (1980-1996)	Ovarian cancer	ALA	RR: 1.00 (0.72-1.39)	Age, parity, age at menarche, oral contraceptive use and duration, menopausal status/postmenopausal hormone use, tubal ligation, and smoking status
				EPA	RR: 0.97 (0.64-1.48)
				DHA	RR: 0.86 (0.55-1.33)
Brasky et al. (2014) [18]	VITamins and lifestyle cohort (United States)	22,494 Women (2000-2010)	Endometrial cancer	ALA	HR: 0.85 (0.56-1.29)	Age, race, education, BMI, pack-years of smoking, physical activity, alcohol consumption, age at menarche, age at first birth, age at menopause, parity, years of combined hormone therapy, years of estrogen-only therapy, years of oral contraceptive use, oophoerectomy, family history of uterine cancer, family history of ovarian cancer, history of diabetes, and total energy
				EPA	HR: 1.73 (1.14-2.63)
				DHA	HR: 1.66 (1.09-2.55)
				EPA+DHA	HR: 1.79 (1.16-2.75)
Brasky et al. (2015) [20]	Women's Health Initiative observational study and clinical trial (United States)	87,360 Postmenopausal women (1993-2010)	Endometrial cancer	ALA EPA DHA DPA EPA+DPA+DHA	HR: 0.96 (0.79-1.18)	Intervention assignment, US region, race, education, BMI, smoking, alcohol, physical activity, age at menarche, age at first birth, age at menopause, parity, duration of combined menopausal hormone therapy, duration of estrogen-alone hormone therapy, duration of oral contraceptive use, oophoerectomy status, family history of endometrial cancer, and history of diabetes
					HR: 0.81 (0.65-1.01)
					HR: 0.77 (0.63-0.95)
					HR: 0.85 (0.69-1.05)
					HR: 0.81 (0.66-1.00)
Brasky et al. (2016) [21]	Black Women's Health Study (United States)	47,602 African-American women (1995-2013)	Endometrial cancer	ALA	HR: 0.86 (0.56-1.33)	Age, time period, and total energy intake, U.S. region, education, BMI, physical activity, alcohol consumption, smoking, fruit consumption, vegetable consumption, age at menarche, age at menopause, parity, age at first birth, duration of combined hormone therapy, duration of estrogen-alone hormone therapy, duration of oral contraceptive use, and diabetes
				EPA	HR: 0.72 (0.47-1.10)
				DHA	HR: 0.84 (0.54-1.30)
				DPA	HR: 0.88 (0.57-1.36)
				EPA+DPA+DHA	HR: 0.79 (0.51-1.24)

OR, odds ratio; RR, relative risk; HR, hazard ratio; CI, confidence interval; ALA, α-linolenic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid.

3. Methodological quality of studies

Table 2 shows the methodological quality of all the included studies based on the Newcastle Ottawa Scale. All the included studies were awarded 7 or 8 stars: three out of five case-controls studies and two out of four cohort studies were given 8. The mean score was 7.6 for case-controls studies and 7.5 for cohort studies.

Table 2.

Methodological quality of studies based on the Newcastle-Ottawa scale

Case-control study (n=6)	Selection				Comparability	Expose			Total
	Adequate definition of cases	Representati veness of cases	Selection of controls	Definition of controls	Comparability of cases and controls	Exposure ascertainment	Same ascertainment criteria for cases and controls	Non-response rate
Bidoli et al. (2002) [14]	☆	☆	-	☆	☆☆	☆	☆	-	7
Tavani et al. (2003) [15]
Lucenteforte et al. (2008) [16]	☆	☆	-	☆	☆☆	☆	☆	-	7
Ibiebele et al. (2012) [17]	☆	☆	☆	☆	☆☆	☆	☆	-	8
Arem et al. (2013) [22]	☆	☆	☆	☆	☆☆	☆	☆	-	8
Merritt et al. (2014) [19]	☆	☆	☆	☆	☆☆	☆	☆	-	8
Cohort study (n=4)	Selection				Comparability	Outcome			Total
	Representati veness of exposed cohort	Selection of non exposed cohort	Ascertainment of exposure	No present of outcome of interest at start of study	Comparability of cohorts	Assessment of outcome	Long follow-up enough for outcomes	Adequacy of follow-up of cohorts
Bertone et al (2002) [13]	-	☆	☆	☆	☆☆	☆	☆	-	7
Brasky et al. (2014) [18]	☆	☆	☆	☆	☆☆	☆	☆	-	8
Brasky et al. (2015) [20]	☆	☆	☆	☆	☆☆	☆	☆	-	8
Brasky et al. (2016) [21]	-	☆	☆	☆	☆☆	☆	☆	-	7

4. Dietary intake of omega-3 fatty acids and risk of endocrine-related gynecological cancer

As shown in Fig. 2, compared to lowest intake of dietary omega-3 fatty acids, highest intake was not associated with the risk of endocrine-related gynecological cancer in the random-effects meta-analysis of case-controls studies (n=5) and cohort studies (n=3) (pooled odds ratio [pOR]/HR, 0.87; 95% CI, 0.73 to 1.04; I2=67.2%). In the meta-analysis by type of study, dietary intake of omega-3 fatty acids was not associated with risk of endocrine-related gynecological cancer in cohort studies (pHR, 1.03; 95% CI, 0.63 to 1.67; I2=81.9%; n=4), while a significantly decreased risk was found in case-control studies (pOR, 0.81; 95% CI, 0.67 to 0.98; I2=55.7%; n=5). No publication bias was observed in the main analysis: the Begg’s funnel plot was symmetrical, and the p for bias from the Egger’s test was 0.41 (Fig. 3).

Fig. 2.

Dietary omega-3 fatty acids intake and risk of endocrine-related gynecological cancer in a random-effects meta-analysis of observational studies by type of study (n=8) [15-22]. OR, odds ratio; HR, hazard ratio; CI, confidence interval.

Fig. 3.

Begg’s funnel plots and Egger’s test for publication bias. OR, odds ratio; HR, hazard ratio; SE, standard error.

Further, there was no significant association between dietary intake of omega-3 fatty acids and endocrine-related gynecological cancer in the subgroup meta-analyses by study quality (low vs. high), type of omega-3 fatty acids (ALA, EPA, DHA, and DPA), and type of cancer and type of study in each type of omega-3 fatty acids (Table 3, Fig. 4).

Table 3.

Subgroup analysis by type of dietary omega-3 fatty acids and study quality

Factor	No. of studies	Pooled OR/RR/HR (95% CI)	I2 (%)
Methodological quality
Low (score of 7 stars) [15,16,21]	3	0.76 (0.55-1.03)	52.7
High (score of 8 stars) [17-20,22]	5	0.93 (0.75-1.66)	72.1
Type of omega-3 fatty acids
EPA [13,17-22]	6	0.88 (0.69-1.12)	69.6
Endometrial cancer [18,20-22]	4	0.86 (0.58-1.30)	81.3
Ovarian cancer [13,17]	2	0.89 (0.73-1.08)	71.5
Case-control study [17,22]	2	0.73 (0.48-1.09)	71.4
Cohort study [13,18-20]	4	0.98 (0.69-1.39)	73.7
ALA [13,14,16-18,20-22]	8	0.96 (0.86-1.06)	39.8
Endometrial cancer [16,18,20-22]	5	0.93 (0.81-1.08)	0
Ovarian cancer [13,14,17]	3	0.99 (0.77-1.26)	58.6
Case-control study [14,16,22]	4	0.97 (0.79-1.18)	39.8
Cohort study [13,18,20,21]	4	0.94 (0.81-1.09)	0
DHA [13,17,18,20-22]	6	0.89 (0.72-1.10)	61.6
Endometrial cancer [18,20-22]	4	0.89 (0.63-1.28)	76.1
Ovarian cancer [13,17]	2	0.91 (0.75-1.11)	0
Case-control study [17,22]	2	0.79 (0.56-1.13)	61.9
Cohort study [13,18,20,21]	4	0.96 (0.69-1.35)	70.7
DPA [17,20,21]	3	0.94 (0.81-1.08)	3.5
Endometrial cancer [20,21]	2	0.86 (0.71-1.03)	0
Ovarian cancer [17]	1	1.06 (0.85-1.33)	NA
Case-control study [17]	1	1.06 (0.85-1.33)	NA
Cohort study [20,21]	2	0.86 (0.71-1.03)	0

OR, odds ratio; RR, relative risk; HR, hazard ratio; CI, confidence interval; EPA, eicosapentaenoic acid; ALA, α-linolenic acid; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; NA, not applicable.

Fig. 4.

Dietary omega-3 fatty acids intake and risk of endocrine-related gynecological cancer in a random-effects meta-analysis of observational studies by type of cancer (n=8) [15-22]. OR, odds ratio; HR, hazard ratio; CI, confidence interval.

Discussion

1. Summary of findings

The current study found that there was no significant association between dietary intake of omega-3 fatty acids and the risk of endocrine-related gynecological cancer in the meta-analysis of cohort studies, while dietary intake of omega-3 fatty acids was associated with the decreased risk of endocrine-related gynecological cancer in case-control studies. These findings imply that there is no higher level of evidence to support the preventive effect of dietary intake of omega-3 fatty acids on endocrine-related gynecological cancer such as endometrial cancer and ovarian cancer.

2. Assessment of bias

The discrepancies in the effect of dietary intake of omega-3 fatty acids on the risk of these cancers between case-control studies and cohort studies might be associated with some important biases [29]. In general, case-control studies are more sensitive to selection bias and recall bias than prospective cohort studies [29]. Either a case group or control group might not represent the whole population because any group was a non-random sample from the population. This could lead to selection bias. Also, cancer patients might recall their dietary differently from controls: for example, they might answer that they had consumed less foods like fatty fish rich in omega-3 fatty acids. On the contrary, healthy people tend to report the healthy dietary habit, which may overestimate the true effect [30].

3. Comparison with previous studies

Our findings are consistent with those from the previous meta-analyses on the similar topic. Qiu et al. [31] reported that polyunsaturated fat intake was not associated with the risk of ovarian cancer in the meta-analysis of case-control studies and cohort studies. Also, Zhao et al. [32] found that there was no association between polyunsaturated fatty acid intake and the risk of endometrial cancer in the meta-analysis of case-control studies and cohort studies.

4. Possible mechanisms

There are several hypotheses regarding the potential protective effect of omega-3 fatty acids on endocrine-related gynecological cancer. A nested case-control study reported that increasing concentrations of CRP, which is a marker of chronic systemic inflammation, were associated the increased risk of ovarian cancer [5]. Another nested case-control study also suggested that CRP levels were positively associated with the risk of endometrial cancer [4]. It has been addressed that there are three overarching mechanisms regarding the pleiotropic anti-inflammatory and immunosuppressive properties of omega-3 fatty acids such as EPA and DHA: modulation of nuclear activation (e.g., nuclear factor-κB), suppression of arachidonic acid-cyclooxygenase-derived eicosanoids, and alteration of the plasma membrane micro-organization (lipid rafts) [33]. Regarding direct anti-carcinogenic mechanisms, previous preclinical models demonstrated that omega-3 fatty acids can reduce tumor cell proliferation, migration, and promote tumor cell apoptosis by inhibiting the mechanistic target of rapamycin complex 1 and 2 signaling, which is one of the major targets for the treatment of endometrial cancer [34]. Also, it has been reported that omega-3 fatty acids had anti-proliferative and anti-carcinogenic effects on epithelial ovarian cancer cell lines [35,36]. However, those anti-cancer effects of omega-3 effects were not observed in our meta-analysis of observational epidemiological studies.

5. Strengths and limitations

To the best of our knowledge, this is the first meta-analysis which reports the associations between dietary intake of omega-3 fatty acids and the risk of endocrine-related gynecological cancers. Our study has several limitations. Firstly, we included a relatively small number of individual studies with six case-control studies and four cohort studies. Thus, further large prospective cohorts studies are warranted to confirm our findings. Secondly, our findings should be limited to dietary intake of omega-3 fatty acids. We planned to evaluate the effects of omega-3 fatty acid supplements on the risk of endocrine-related gynecological cancer. However, when we searched three core databases (PubMed, EMBASE, and Cochrane Library), only VITAL study [18] reported the result which source of omega-3 fatty acids is from diet plus supplement. Thirdly, among studies included in the analyses, only Brasky’s study takes into consideration of dietary factors as adjustment variables. Lastly, our results were not able to be applied to Asians because published data originated from the Western countries, mainly the United States, and different methods of fish cooking between Western and Eastern countries and frequent intakes of raw fish in Far Eastern countries such as Japan and Korea as a source of dietary omega-3 fatty acids may affect the risk of endocrine-related gynecological cancer.

In conclusion, the current meta-analysis of observational studies suggests that there was no higher level of evidence to support the protective effect of dietary intake of omega-3 fatty acids on the risk of endocrine-related gynecological cancer such as endometrial cancer and ovarian cancer. Further larger prospective studies should be necessary to confirm our findings.