Safety and efficacy of docosahexaenoic acid supplementation during neoadjuvant breast cancer therapy: Findings from the phase II, double-blind, randomized controlled DHA-WIN trial

Abstract

There is limited clinical evidence of docosahexaenoic acid (DHA) efficacy during breast cancer neoadjuvant chemotherapy (NAC). This randomized, double-blind, placebo-controlled trial aimed to investigate the safety and efficacy of DHA supplementation in breast cancer patients undergoing NAC. Participants (n = 49) were assigned to receive either DHA 4.4 g/day orally (algae triacylglycerol) or a placebo (corn/soy oil) over six cycles (18 weeks) of NAC. The primary outcome was the evaluation of changes in the percentage of Ki-67 expression, assessed by immunohistochemistry analysis from pre- to post-treatment. Secondary outcomes included pathological complete response, incidence of adverse effects, and 3-year survival analysis. Compliance was evaluated by fatty acid analysis of plasma phospholipids and erythrocyte total lipids quantified by gas-liquid chromatography. The expression of Ki-67 significantly decreased in both groups, with no significant effects of the DHA intervention (p = 0.38). When stratified by breast cancer subtype, there was a trend of greater reduction in Ki-67 expression in the human epidermal growth receptor 2 (HER2+++) subtype in the DHA group compared to placebo (p = 0.1). The % of DHA in erythrocytes and plasma phospholipids was increased by two-fold at 9 and 15 weeks of therapy in the DHA group, while it remained unchanged in the placebo group (p-interaction <0.001). There was no reported incidence of adverse effects related to the intervention, and no significant effects were found in the other secondary outcomes. NAC significantly decreased the expression of Ki-67, with no additional beneficial effects observed by DHA supplementation. Further research is necessary to confirm these findings.

Keywords: Ki‐67; Omega‐3; human epidermal growth factor receptor 2; long‐chain polyunsaturated fatty acids; pathological complete response; triple negative breast cancer.

FIGURE 1

CONSORT flow diagram. Adverse events included (n = 13): Nausea (n = 9), severe pain (n = 2), elevation of liver enzymes (n = 1), and critically low hemoglobin (n = 1). Other reasons for discontinuation included (n = 12): Disease progression; early surgery requested (n = 2); metastatic disease (n = 4); refusal to take the study intervention or difficulty cooperating with the study (n = 4); gallbladder disease followed by physician's decision to remove the patient from the study (n = 1); and dose‐dense chemotherapy (n = 1).

FIGURE 2

Changes in the expression of the proliferation marker Ki‐67. (A) Changes from pre‐ to post‐intervention considering all participants with complete data. (B) Comparison of the change in Ki‐67 expression between pre‐ and post‐intervention within each subgroup. (C) Comparison of the change in Ki‐67 expression from pre‐ to post‐intervention between the groups. (D) Comparison of the change in Ki‐67 expression between pre‐ and post‐intervention within each subgroup in participants classified as HER2+++ subtype as classified by histopathological analysis. (B–D) Bars represent mean and 95% confidence interval. HER2+++, human epidermal growth receptor positive; NAC, neoadjuvant chemotherapy.

FIGURE 3

Forest plot of univariate analysis of associations between different predictors and pathological complete response (pCR) irrespective of treatment arm. The continuous variables were age, BMI, change from baseline to end of chemotherapy (delta) %Ki‐67, TSR, while categorical variables included ER status (negative vs. positive), PR status (negative vs. positive), HER2 status (negative vs. positive), menopausal status (negative vs. positive), and disease stage (low vs. high). BMI, body mass index; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; TSR, tumor‐stroma ratio.

FIGURE 4

Survival analysis at approximately 3 years after randomization (n = 21 in each group). Disease‐free survival (A) and overall survival (B) in months were analyzed using the Kaplan–Meier method. The mean survival was undetermined due to the small incidence of events (disease recurrence or death).