The effectiveness of omega‐3 fatty acids on health outcomes in women with breast cancer: A systematic review

Abstract This study aimed to systematically evaluate the impact of omega‐3 fatty acids on the health outcomes of women with breast cancer in electronic databases (PubMed, Scopus, ProQuest, Web of Science, and Cochrane Library) for interventional studies. The risk of bias and the quality of the included articles were assessed by Cochrane Collaboration Handbook guidance. The statistical analyses were not conducted because of the heterogeneity of the included studies. Of 3676 identified articles, 11 articles were included in this study. The majority of the included studies were not of high quality. Median progression time and overall survival significantly improved. Additionally, surgical site healing complications and infection rates decreased. There was a significant decrease in perceived stress, sleep disturbance, depression, pain, joint stiffness, and fatigue throughout the intervention. Moreover, omega‐3 fatty acids consumption significantly increased the total serum omega‐3, EPA, and DHA, and decreased the omega‐6: omega‐3 ratio, total leukocytes, lymphocytes, leptin, and CRP, accordingly. Mild gastrointestinal symptoms were reported in only two studies without clinically relevant adverse events. Omega‐3 fatty acids may cause improvement in physical, mental, and some inflammatory and metabolic indices during treatment or posttreatment course of breast cancer patients. Due to the possibility of free radical formation, omega‐3 FAs supplementation and consumption must be done very carefully.

therapeutic strategies for BC are chemotherapy, surgery, radiotherapy, immunotherapy, hormone therapy, and gene therapy (Arruebo et al., 2011). However, the toxicity of antineoplastic treatments affects the patient's quality of life. The therapeutic intervention also causes short-term and long-term side effects such as fatigue, dizziness, constipation, appetite decrease, nausea, vomiting, and cardiotoxicity (Partridge et al., 2001;Shapiro & Recht, 2001).
In this regard, recent studies have reported the effectiveness of complementary medicine on the improvement of treatment results in different cancers with minimal side effects. Hence, co-adjuvant therapies are of profound interest (Gerber et al., 2006;Hübner et al., 2021;Zhu et al., 2016).
Omega-3 fatty acids (omega-3 FAs) supplementation is considered an adjunctive treatment to reduce toxicity and improve disease outcomes (Laviano et al., 2013). Omega-3 FAs play an important role in cell membrane structure, fluidity, and cell signaling (Calder, 2011).
Some studies have shown that dietary omega-3 polyunsaturated fatty acids (PUFAs) reduce the development of cancer, including BC (Bartsch et al., 1999;Chen et al., 2007;Turk & Chapkin, 2013). It has been reported that the aberrant expression of enhancer of zest homologue 2 (EZH2) is associated with metastasis and poor outcomes in cancer patients. In this regard, unsaturated omega-3 FAs consumption causes EZH2 regulation in BC (Dimri et al., 2009). A chronic inflammatory status leads to tumor initiation, growth, and metastasis (Hammad et al., 2021). Omega-3 FAs reduce cytokine production, decrease cell proliferation and tumor growth, as well as increase the apoptosis process. Some studies have also shown that omega-3 FAs play an essential role in anti-inflammatory actions (Calder, 2013;Mori & Beilin, 2004;Schley et al., 2005;Yenipazar & Şahin-Yeşilçubuk, 2022). Moreover, omega-3 supplementation increases the skeletal muscle index, energy balance, and overall survival (OS), while reducing xerostomia, inflammation, and toxicity of chemotherapy. In the Ambrosone et al. (2020) study, the use of omega-3 FAs both before and during chemotherapy was associated with disability-free survival (DFS) but no significant improvement was observed regarding OS. Some studies have also shown that omega-3 FAs have a positive effect on the immune system (Bird et al., 2021;Darwito et al., 2019;de la Rosa Oliva et al., 2019;Ma et al., 2021).
Inflammation in cancer patients may be associated with complications such as pain and depression. Depression is another common problem affecting 8%-24% of cancer patients. It is assumed that the depletion of omega-3 FAs in cell membranes is of etiological importance in depression. Some studies supported the antidepressant properties of omega-3 FAs consumption (Chiu et al., 2003;Krebber et al., 2014;Maes & Smith, 1998). Peripheral neuropathy is a common side effect of many chemotherapeutic patients. Additionally, omega-3 FAs may be effective in the prevention of paclitaxelinduced neuropathy (PIPN) in women with BC who undergo chemotherapy and increase the quality of life in these patients (Ghoreishi et al., 2012).
Although omega-3 supplements have no side effects during chemotherapy and can improve chemotherapy outcomes when highly incorporated (Bougnoux et al., 2009), another study reported mild gastrointestinal tract (GIT) discomfort (Martínez et al., 2019). It should be noted that when prescribing omega-3 PUFAs, side effects should be considered. In this regard, the results of a study showed no short-term complications after omega-3 PUFAs consumption; however, long-term PUFA supplementation may be associated with an increased risk of cancer, possibly due to their oxidation products or added antioxidants (Lange et al., 2019). On the other hand, the source of omega-3 FAs may be important in acquiring positive outcomes. The results of a study showed a reduced risk of recurrence after colon cancer diagnosis following omega-3 PUFAs following fish consumption and not supplements (Van Blarigan et al., 2018).
Despite the numerous benefits of omega-3 FAs, previous systematic reviews have been limited in the lack of comprehensive literature on the health outcomes of women with BC. Therefore, the aim of the current systematic review was to summarize the effect of omega-3 FAs supplementation on physical and psychological outcomes, as well as metabolic indices in women suffering from BC.

| MATERIAL S AND ME THODS
This systematic review was performed according to the guidelines of the Cochrane Handbook for systematic reviews of interventions (Higgins et al., 2022) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA; Shamseer et al., 2015). In this study, all the interventional studies consisted of randomized controlled trials (RCTs), and quasi-and semi-experimental articles that investigated the effect of supplementation with omega-3 FAs on the health outcomes of women with BC were studied.

| Inclusion criteria
In this survey, the PICOS criteria including participants, intervention, comparison, outcomes, and study design were used. The participants included women with BC under medical treatment or in received-treatment follow-up state. The intervention comprised the use of omega-3 FAs supplements or consuming foods enriched with omega-3 FAs sources. The comparison included any control group such as a placebo, any other known supplements, or without intervention. Outcomes included any health outcomes of supplementation such as physical, mental, and metabolic outcomes. The study design included RCTs, quasi, and semi-experimental studies.
Omega-3 FAs could be administered during any medical treatment such as surgery, chemotherapy, radiation, and their combination, or during the follow-up of BC survivors' medical treatment. All the related articles on BC patients at any stage were included. Omega-3 FAs supplements in any form, fish oil, docosahexaenoic acid (DHA), EPA, and alpha-linolenic acid (ALA), etc., at any dose, by any route (oral or enteral), at any duration and dose interval, solely or in combination with other nutrients, were included in this review. Dietary interventions through consuming foods enriched by omega-3 FAs sources were also incorporated. There was no age restriction.

| Exclusion criteria
Review articles, animal studies, cellular and molecular studies, study protocols, cross-sectional studies, cohorts, case-control, case reports, case series, letters to the editor, and editorials were excluded. In order to manage the findings of the search by the mentioned strategies, Endnote X8 software (Thomas Reuters) was employed.

| The strategy of articles search and study selection
Two independent review team members (AMH and ShO) independently assessed the eligibility of publications on the efficacy of omega-3 PUFAs in BC patients by reviewing the title and abstract of identified studies. During the screening of the articles, the disagreements were resolved through discussion with a third reviewer (AFKh). This process continued for the screening of full texts.

| Data extraction
The three reviewers (AFKh, AMH, and ShO) extracted the data from all eligible studies. They transferred the necessary information into an electronic form designed for this review consisting of the following sections: authors name and the year of publication, country of study, study design, objectives, evaluated outcomes, the number of participants, intervention and control groups, follow-up period, study results and possible side effects (Tables 1 and 2).

| Assessment of methodological quality
The risk of bias and quality of the included articles were assessed through the guidance of the Cochrane Collaboration Handbook by two members of the review (AFKh & AMH). The following items were assessed: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and selective reporting (reporting bias). Disagreements were resolved through discussion with a third party (ShO). The bias of the studies was demonstrated using Review Manager 5.3 (RevMan; The Cochrane Collaboration, Oxford, UK) software.

| Data synthesis
Data were synthesized through qualitative approaches and reported as a systematic review because there were inadequate data for data pooling. Three articles were single-arm interventional studies. The remaining eight studies had not enough similar outcomes to meta-analysis.

| Literature search and selected articles
Details of the search process and article selection, as well as the reasons for article exclusion, are presented in Figure 1. Of 3676 identified articles in the search of various databases, 1752 articles were removed from the study as duplications, and the rest of the trials were screened to evaluate the eligibility criteria. Among the reviewed 1924 articles, 1904 was excluded due to not being an interventional study (n = 1305), not being a human study (n = 352), being a study protocol (n = 21), investigating other neoplasms (n = 195), and intervention by supplements other than omega-3 FAs or compounds containing them (n = 31). Although 20 studies were selected for systematic review by surveying the title and abstract of the articles, after reviewing the full texts, 11 articles were eligible and finally included in this systematic review.

| Description of the studies
The selected trials in this systematic review have been published from 2009 to 2022. Of the 11 articles reviewed, 10 articles had full English text (Bjørklund, 2015;Bougnoux et al., 2009;Darwito et al., 2019;de la Rosa Oliva et al., 2019;Kahlenberg et al., 2020;Kleckner et al., 2021;Martínez et al., 2019;Paixão et al., 2017;Shen et al., 2018;Xu et al., 2022) and one article had English abstract (DelaRosa-Oliva et al., 2017). Among included articles, eight studies were RCTs and three of them were single-arm uncontrolled before-after trials (Bjørklund, 2015;Bougnoux et al., 2009;Martínez et al., 2019). In addition, four articles were conducted in the United States (Kahlenberg et al., 2020;Kleckner et al., 2021;Shen et al., 2018;Xu et al., 2022), two articles in Mexico (de la Rosa  Weight and BMI: no significant differences were observed following intervention Cardiometabolic profile TG "Significant increase in the concentration of TGs at three and six months (p = .0001) was found in both groups." Cholesterol "Cholesterolemia was significantly higher at three and six months (p = .04), but no differences were found when comparing the effect of the supplementation with PUFA Ω-3 vs. placebo." HDL "HDL presented a significant reduction in both groups (p = .0001); this effect was not significant when it was compared between the two groups." Serum albumin showed a statistically significant reduction (p = .0001), however, this effect was not significant in relation to PUFA Ω-3 or placebo groups.

Liver assessment
Albumin "Serum albumin showed a statistically significant reduction (p = .0001), however, this effect was not significant in relation to PUFA Ω-3 or placebo groups." ALT(alanine aminotransferase) "The two groups show an increase considered to be still normal, which was significant at three and six months (p = .002)"  Tables 1 and 2 & Table S2.

| Risk of bias in the included studies
The methodological quality based on the researchers' decision on every risk of bias for each included article is illustrated in Figures 2   and 3. The majority of the included studies were not of high quality. Bjørklund (2015) investigated the possibility of a synergistic effect of various categories of nutritional supplements including essential fatty acids (after 18 months). They reported that none of the patients had died during the study period. None of them showed signs of further distant metastases. The quality of life was improved (no weight loss and reduced use of painkillers). Subsequently, there were some cases of death, but not more than 5 or 6 (while 16 deaths were expected from historical controls) after 4.5 years.

TA B L E 1 (Continued)
TA B L E 2 The characteristics of the included studies investigating the effect of n-3 fatty acids following primary medical treatment on the health outcomes of breast cancer patients. Low omega-3LC group had trends of symptom improvement; however, the difference did not reach statistical significance.  (Tables 1 and 2).

| DISCUSS ION
This study aimed to review the existing studies on the effect of omega-3 FAs on health outcomes in BC patients under therapeutic regimens. Overall, the results of the present study indicated the positive effects of these FAs on treatment outcomes. However, some studies reported no significant changes or side effects in studied parameters after taking omega-3 FAs in BC patients.
Omega-3 FAs are essential fatty acids with diverse potential biological effects. In recent decades, the benefits of these fatty acids on health outcomes have also been further studied. Due to the presence of two or more unsaturated bonds, these fatty acids possess an unstable structure, enabling them to keep the suitable membrane fluidity and related signaling. However, high temperature, oxidation, and hydrogenation will result in free radicals formation from omega-3 FAs, which are harmful mediators in the human body F I G U R E 1 Diagram for the search and selection process of the articles considered in this review. (Yashodhara et al., 2009 Bonetti et al. (1996), higher cell proliferation may be associated with improved response to chemotherapy in a short time.
Omega-3 supplementation in Darwito et al. (2019) study led to increased Ki-67 and VEGF after 48 weeks of follow-up, which was also associated with increased OS and PFS in the studied population. In a short time, this effect may be beneficial, however, long-term follow-up is needed to better evaluate the effect of this supplementation on patients' OS and PFS.

| The limitations of the studies and the need for further research
The included studies had some limitations, which necessitate further research regarding the effects of omega-3 FAs supplementation in BC patients under chemotherapy regimens. Included studies were different in study design, type of BC, chemotherapy regimen, patient's BMI, disease staging, used omega-3 FAs dose, supplementation duration, and sample sizes. Additionally, ethnic differences were another confounding factor, which may affect the results of the study. Moreover, included studies evaluated different parameters which make it difficult to compare the outcomes of the omega-3 FAs supplementation in BC. Due to the mentioned limitation, it was impossible conducting a meta-analysis for this systematic review.
Considering the above-mentioned limitations, further research regarding the effect of omega-3 FAs on health outcomes in BC patients under chemotherapy is suggested. This review focused on human articles and, as such, it is suggested that a review be made on animal subjects in this field.

ACK N OWLED G M ENTS
The authors thank the Tabriz University of Medical Science for providing the instrumental and research facilities for completing this work. We would also like to appreciate the cooperation of the Clinical Research Development Unit of Imam Reza General Hospital, Tabriz, Iran in conducting this research.

F I G U R E 3
Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.