Other than skin cancer, prostate cancer (PCa) is the most common cancer in American men [1]. In 2025, it is estimated that 313,780 new cases of prostate cancer will be diagnosed in the US and 35,770 men will die of this disease ACS [2]. Despite several advances in the early detection, treatment, and clinical management of prostate cancer in recent decades, much work is still needed to fully understand the risk factors for prostate cancer that can result in the development of strategies to address these risk factors by implementing validated preventive approaches targeting men at high risk or with early-stage disease. Metastatic castration resistant PCa is still a fatal disease [1], [2]. Known risk factors for prostate cancer development include age, race, ethnicity, family history, hormonal factors, diet, obesity, and physical activity [3], [4], [5], [6], [7], [8], [9], [10], [11], [12].

Several nutrients and nutrient-derived substances have been evaluated as dietary interventions or as bioactive compounds in vitro, preclinical and in early clinical trials [13], [14]. Some of the compounds and nutritional approaches evaluated to date include specific diets rich in vegetables and fruits [15], low fat diets [16], vitamins D [17], [18], [19], Vitamin E [20], [21], green tea catechins [22], [23], soy isoflavones [24], [25], [26], lycopene [27], [28], Selenium [20], [29], pomegranate [30], and resveratrol [31], [32]. However, to date, the results of these trials have been mixed, potentially due to limitations in validated endpoints, measurement of exposure, target populations, duration of intervention and studies that are underpowered. Thus, currently, there are no nutritional approaches or nutrient-derived agents/bioactive compounds that have been identified as safe and effective to reduce risk or prevent progression of prostate cancer in clinical settings, underscoring the need to continue to identify agents/approaches to reduce risk and prevent progression of PCa.

Omega-3 (ω-3) polyunsaturated fatty acids (PUFA’s) -specifically from nutritional sources – eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to exert a variety of anti-tumor effects including inhibition of several proliferative pathways, induction of apoptosis, reduction of angiogenesis and anti-inflammatory effects [33], [34]. Research has demonstrated that the mechanisms involved include suppression of nuclear factor-κB (NF-κB), activation of AMPK/SIRT1, modulation of cyclooxygenase (COX) activity, and up-regulation of novel anti-inflammatory lipid mediators such as protectins, maresins, and resolvins [35], [36]. In a study performed on human prostate adenocarcinoma cell lines found that exposure to DHA attenuated the NF-κB survival pathway, as well as lowered levels of survivin, a protein involved in inhibition of apoptosis, thus arresting cancer growth [37]. ω-3 FA and ω −6 FA have opposing roles in contributing to inflammatory pathways. The main dietary ω-3 FA include alpha linolenic acid (ALA), DHA, and EPA. These molecules or their derivatives are modulated by cyclooxygenase (COX) enzymes, which also are responsible for enzymatic reactions on arachidonic acid, derived from omega-6 FA. Unlike ω-3 FA, the omega-6 pathway produces various pro-inflammatory molecules. A study targeting PTEN knockout mice found that diets high in ω-3 FA in the mouse model were able to promote apoptosis by increasing cellular levels of BAD (a pro-apoptotic protein), lowering its phosphorylation, and significantly increased survival of the PTEN knockout mice over a 12-month period [38]. Other have shown that ω-3 FA enriched diet decreased prostate TRAMP-C2 tumor growth in immune-competent eugonadal and castrated mice demonstrating that ω3 FA can inhibit tumor cell growth and induce a local anti-tumor inflammatory response, independently of androgen levels [39].

Epidemiologic studies have shown that populations that consume higher amounts of marine-derived ω-3 FA, including Japanese and Alaskan Natives, have lowered risk for the development of PCa [40]. In a prospective cohort of 47 866 US men aged 40–75 followed for 14 years, results demonstrated a decreased risk of PCa with ω-3 FA intake [41]. In a recent meta-analysis, the dose-response association between fish intake and prostate cancer was determined. In the dose-response analyses, each 20 g/day increase in total fish intake was associated with a 12 % lower risk of prostate cancer mortality, supporting the protective association between total fish intake and the risk of prostate cancer mortality [42]. On the other hand, in a prospective trial [SELECT] [43], high plasma phospholipid concentrations of long-chain ω-3 PUFA were associated with statistically significant increases both low- and high-grade disease and for EPA, DPA and DHA, although, these ω-3 FA have been shown to be anti-inflammatory, metabolically interrelated ω-3 fatty acids derived from oily fish and fish oil supplements. Comparable results have been reported in several meta-analysis with three supporting the observations in the SELECT cohort with another reporting an inverse association [44], [45], [46]. Among interventional trials in PCa, prostate specific antigen (PSA) levels remained unchanged despite fish oil supplementation; however, in 2 of these interventional trials, reductions in either cell-cycle progression score or reduction in epithelial cell proliferation were noted [34]. In a randomized clinical trial from biopsy to prostatectomy (n = 48), a 4–6-week low-fat diet and 5 g fish oil capsules/day to achieve an ω-6: ω-3 FA ratio of 2:1 resulted in decreased prostate cancer proliferation and decreased prostate tissue omega-6:omega-3 ratios [47]. In a study to evaluate associations between grade reclassification and ω3 levels assessed in prostatic tissue, red blood cells (RBC), and diet. Results indicated that high long-chain (LC) ω3-eicosapentaenoic acid (EPA) level in prostate tissue and LCω3 dietary intake was associated with lower odds of high-grade PCa. LCω3-EPA levels in the target prostate tissue as well as intake are inversely associated with high-grade PCa in men with low-risk PCa [48]. In a meta-analysis evaluating the association of n- 3 FA and PCa risk, the data was reported to be insufficient to suggest a relationship between fish-derived ω-3 fatty acid and risk of PCa [49]. Others have reported comparable results [50].

Despite promising laboratory and pre-clinical data, the overall evidence for the ability of ω-3 fatty acid intake to prevent PCa development, severity, and progression remains inconclusive due to the conflicting results of studies in humans. Based on laboratory and pre-clinical data and lack of clear evidence in observational studies, we hypothesize that patients with higher intake of ω-3 fatty acid prior to diagnosis will have lower grade prostate tumors as determined by Gleason score at diagnosis compared to those men who consume relative lower quantities of ω-3 FA. The hypothesis was tested using the following specific aims. In newly diagnosed men with prostate cancer (between 2020 and 2021), we obtained dietary and supplementary use of ω-3 fatty acid in the past 6 months, using a validated food frequency questionnaire, and evaluated if quantity of intake of ω-3 FA is associated with grade of prostate cancer at diagnosis, taking into account other comorbidities known to be associated with prostate cancer risk (race, age, obesity and other lifestyle factors).