Docosahexaenoic Acid (DHA) for Women With Breast Cancer in the Neoadjuvant Setting

Summary

Docosahexaenoic acid (DHA) is an omega-3 long chain polyunsaturated fatty acid (n-3 LCPUFA). N-3 LCPUFA are essential fatty acids in the diet. The majority of n-3 LCPUFA in the diet is alpha-linolenic acid (ALA). While DHA can be synthesized from ALA and other n-3 LCPUFA in the body, endogenous synthesis is low. Consequently, the only way to significantly increase levels of DHA in tissues is by directly consuming this fatty acid. Common sources of DHA are fatty fish, fish oil and omega-3 supplements and fortified foods.

DHA is readily incorporated into membrane phospholipids and induces changes in the properties of the cell membrane including altered fluidity; permeability and membrane transport as well as activity of membrane bound receptors and enzymes.

It is well established that changes in membrane DHA has multiple effects in the body, including modulation of neurological, immune, and cardiovascular functions. In breast cancer, DHA increases sensitivity of breast cancer cells to different chemotherapeutic agents, and in animal models of breast cancer, dietary DHA decreases tumour growth. The investigator's preclinical studies demonstrate that DHA increases efficacy of both doxorubicin and docetaxel, two agents commonly used in the adjuvant setting for breast cancer treatment. Furthermore, DHA mitigates chemotherapy induced weight loss in mice, and reduces paclitaxel toxicities in breast cancer patients, strongly indicating that DHA protects against toxicity in normal tissues. Directly relevant to this study, increased DHA in breast adipose tissue correlates with improved response to chemotherapy, and increased dietary intake of n-3 LCPUFA, including DHA, results in increased DHA incorporation in breast adipose tissue. Lastly, in advanced metastatic breast cancer, DHA supplementation correlated with improved outcomes in a subset of patients. Consequently, the Investigators hypothesize that the therapeutic index (efficacy: toxicity ratio) will be improved with the addition of DHA. In this clinical trial, the Investigators will explore the benefit of DHA supplementation in combination with neoadjuvant chemotherapy in patients with early breast cancer.

RESEARCH QUESTION \& OBJECTIVES: The Investigators propose to evaluate incorporation of DHA in women with breast cancer in treatment naïve patients in combination with chemotherapy, and assess potential benefit of DHA supplementation in breast cancer patients, using change in Ki67 labeling index (marker of proliferation) as a marker of efficacy. This study will further investigate the relationship between DHA in plasma phospholipids (as a potential biomarker of tumour incorporation) and effect on systemic immune function.

METHODS: Patients directed to receive chemotherapy will receive capsules, each containing a minimum of 400 mg of DHA in the form of DHA enriched triglyceride oil or placebo (corn/soy oil blend) to be taken orally (11 capsules/day, throughout day as preferred by participant) for a total of 5 g DHA or placebo, for 12-18 weeks (84-126 days) beginning at the start of the first cycle of chemotherapy, and continued throughout 4-6 cycles of chemotherapy (3 weeks/ cycle). DHA will be discontinued 21 days after the last administration of cytotoxic chemotherapy. Tumour biopsies at baseline and post surgical removal will be assessed for Ki67 status as well as for markers of apoptosis and stem cell presence (by immunohistochemistry). Blood samples taken at baseline prior to each round of chemotherapy will be assessed for immune markers and plasma phospholipid content.

Conditions

• Breast Cancer

Interventions

DIETARY_SUPPLEMENT

Docosahexaenoic acid (DHA)

Participants will take 11 capsules of DHA oil for 12-18 weeks (84-126 days), beginning on day 1 of initial cycle of chemotherapy, and continuing for 4-6 cycles of chemotherapy prior to definitive breast surgery. Study will end when subject undergoes breast surgery.

DRUG

Placebo oral capsule

Participants will take 11 capsules of placebo (corn/soy oil blend) for 12-18 weeks (84-126 days), beginning on day 1 of initial cycle of chemotherapy, and continuing for 4-6 cycles of chemotherapy prior to definitive breast surgery. Study will end when subject undergoes breast surgery.

Sponsors & Collaborators

• Canadian Institutes of Health Research (CIHR)

  collaborator OTHER_GOV

• University of Alberta

  collaborator OTHER

• AHS Cancer Control Alberta

  lead OTHER

Principal Investigators

• John Mackey, MD · Cross Cancer Institute

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

FEMALE

Healthy Volunteers

No

Timeline & Regulatory

Start

2019-08-28

Primary Completion

2024-12-01

Completion

2030-09-30

Countries

• Canada

Study Locations