Mediterranean Diet and Inequality in Early Breast Cancer: A Multicenter Randomized Clinical Trial
Trial Snapshot
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- Enrollment
- 105
- Locations
- 3
- Primary Endpoint
- Change in microbiota composition
Study Overview
Brief Summary
Social determinants such as education, income, marital status, and social networks play a crucial role in cancer outcomes, including breast cancer. One potential influencing factor is diet, and the Mediterranean diet has been shown to benefit both the health and the microbiome.
This raises the question: Does adherence to the Mediterranean diet impact the microbiome, quality of life, overall well-being, and outcomes in breast cancer patients undergoing (neo)adjuvant treatment, particularly among those with unfavorable socioeconomic determinants?
The Mediterranean diet consists of plant foods such as vegetables, fruits, nuts, seeds, berries, legumes, herbs, and spices. It also features animal proteins like fish, meat, and cheese, along with fat from olive oil. Thus, adherence to the Mediterranean diet is adherence to the official Danish diet recommendations.
This phase II clinical trial is an interdisciplinary study combining nutrition, sociology, and health research. Breast cancer patients candidates for (neo)adjuvant treatment at four oncology departments in Region South Denmark will be randomized 2:1 to the Mediterranean diet (with individual dietary guidance from a nutrition therapist aiming at daily consumption of a minimum of 30 grams of dietary fiber and weekly consumption of a minimum of 30 different plant foods; minimizing the amount of ultra-processed food) versus the patient's regular diet, in conjuction with the (neo)adjuvant chemotherapy.
The trial's primary endpoint will be changes in gut microbiota composition in feces.
The study evaluates how the Mediterranean diet affects the microbiota (evaluated using Oxford Nanopore Technology 16S sequencing on fecal samples); short-chain fatty acids in stool and plasma (assessed by mass spectrometry); immune system (using flow cytometry for immune cell determination in blood and immunohistochemical determination of immune cells in the tumor tissue); and patients' social quality of life, overall well-being, sense of empowerment, and personal feeling of agency (using the WHOQOL-100 questionnaire); taking into account the impact of the distance from the patient residence to the hospital (tracked from GEOTEAM at Statistics Denmark), and socioeconomic factors (using the DREAM database).
The evaluation of biological parameters is based on the suggested mechanism of action. A diet rich in various plant foods and dietary fiber will alter the gut microbiota, promoting bacteria producing high amounts of short-chain fatty acids. These fatty acids will activate immune cells, aiding in the destruction of cancer cells.
The study will also assess whether the Mediterranean diet will positively impact the patients' social quality of life, overall well-being, sense of empowerment, and personal feeling of agency. The Mediterranean diet may not only lead to improved dietary habits but also serve as a crucial tool for breast cancer patients, particularly among those with unfavorable socioeconomic determinants. Enhanced empowerment and improved coping tools could be an important step in combating cancer-related inequalities.
Detailed Description
STUDY PURPOSE The project investigates whether adherence to the Mediterranean diet can influence the microbiome, improve quality of life, overall well-being, sense of empowerment, personal feeling of agency, immune activity, levels of short-chain fatty acids and patient outcomes in breast cancer patients undergoing chemotherapy. Additionally, it examines if these effects are more pronounced in individuals with challenging socioeconomic determinants.
BREAST CANCER Among women, breast cancer is the most diagnosed cancer, and is the leading cause of cancer deaths globally in most countries, with 2.3 million new cases recorded in 2022 and approximately 665,000 deaths. In Denmark, there are 5000 new cases, and 1.050 deaths annually, of those 250 in the Region of Southern Denmark. In men, breast cancer is rare with an average of 42 new cases annually in Denmark.
ONCOLOGICAL TREATMENT The oncological treatment of early breast cancer encompasses neoadjuvant (pre-surgery) and adjuvant (post-surgery) treatments.Chemotherapy comprising anthracyclines and taxanes is a cornerstone in both neoadjuvant and adjuvant settings for breast cancer treatment. These drugs have been shown to significantly improve patient outcomes as these regimens are particularly effective in shrinking tumors before surgery, reducing the risk of recurrence and improving overall survival. HER2-targeted therapies, such as trastuzumab, are specifically used for HER2-positive breast cancers in conjunction with chemotherapy and have significantly improved outcomes. Recently, checkpoint immunotherapy, pembrolizumab, has been approved in Denmark for triple-negative early breast cancer together with chemotherapy due to increased pathological complete response (pCR).
SOCIOECONIC INEQUALITY At the national level, disparities in breast cancer outcomes are commonly observed along socioeconomic and demographic lines in both low-, middle- and, high-income countries. These disparities are evident across all stages of the breast cancer continuum, from exposure to modifiable risk factors to access to palliative care and mortality rates. Consequently, women with lower socioeconomic status are more likely to present with late-stage cancer and experience poorer breast cancer prognoses compared to those with higher socioeconomic status. Cancer inequalities at the individual level are predominantly shaped by systemic social determinants of health.
In Denmark an estimated 21% of breast cancer deaths five years after the diagnosis of breast cancer could have been avoided, had patients in all income groups had the same survival rate as the high-income group. Thus, social inequality in cancer survival is a critical problem, and patients with little education, low income, or living alone have poorer survival than better educated cancer patients, with higher income, and living in a relationship. This applies despite women with higher socioeconomic status having significantly higher breast cancer incidence.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Masking Description
Open Label
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Signed written informed consent approved by the Ethical Review Board.
- •Histologically confirmed unilateral adenocarcinoma of the breast, stage I-III, candidates for neoadjuvant chemotherapy followed by curative surgery, or adjuvant chemotherapy after curative surgery, according to the Danish Breast Cancer Group guidelines
- •The addition of trastuzumab and pertuzumab in HER2-positive tumors, or pembrolizumab in triple-negative tumors, per Danish Breast Cancer Group guidelines 48, is allowed as an adjunct to chemotherapy.
- •Good performance status (WHO performance status 0 or 1).
- •Willingness by the patient to undergo treatment and study-related procedures according to the protocol.
- •Have a smartphone or computer to which it is possible to receive emails (for food diary; www.myfood24.org)
- •Must be willing to restrict from probiotic (living microorganisms) supplements during the study. Fermented foods are allowed.
Exclusion Criteria
- •Clinical or radiological signs of metastatic disease.
- •History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or non-melanoma skin cancer.
- •Previous chemotherapy for cancer or other malignant disease.
- •Major altered digestive system disorders (e.g. gastric by-pass or Crohn's disease or ulcerative colitis)
- •Unable to communicate effectively in Danish or English.
Arms & Interventions
Mediterranean Diet
The intervention is the Mediterranean Diet.
Intervention: The goal is daily consumption of a minimum of 30 grams of dietary fiber and weekly consumption of a minimum of 30 different plant foods; minimizing the amount of ultra-processed food. (Dietary Supplement)
Standard Diet
The control group will continue their normal diet.
Intervention: Standard Diet (Other)
Outcomes
Primary Outcomes
Change in microbiota composition
Time Frame: Baseline to Day 1 of chemotherapy cycle 6. Each cycle is 3 weeks for regular schedule or 2 weeks for accelerated schedule, as per clinician decision.
The primary objective of this trial, assessing the clinical efficacy of the Mediterranean diet, is changes in gut microbiota composition, analyzed as microbial differential abundance (measures the difference in the abundance of specific microbial taxa between groups) by the ZicoSeq differential abundance analysis method, accounting for multiple-testing using the false discovery method (FDR). The endpoint will be measured at cycle 6 and compared with baseline values, in patients allocated to the Mediterranean Diet compared to patients on their regular diet.
Secondary Outcomes
- Change in alpha diversity in stool samples(Baseline to Day 1 of chemotherapy cycle 6. Each cycle is 3 weeks for regular schedule or 2 weeks for accelerated schedule, as per clinician decision.)
- Change in beta diversity in stool samples(Baseline to Day 1 of chemotherapy cycle 6. Each cycle is 3 weeks for regular schedule or 2 weeks for accelerated schedule, as per clinician decision.)
- Level of short-chain fatty acids in stool and plasma(Baseline to Day 1 of chemotherapy cycle 6. Each cycle is 3 weeks for regular schedule or 2 weeks for accelerated schedule, as per clinician decision.)
- Quality of life measured by WHOQOL-questionnaire(Baseline to Day 1 of chemotherapy cycle 6. Each cycle is 3 weeks for regular schedule or 2 weeks for accelerated schedule, as per clinician decision.)
- Socioeconomic factors and quality of life correlated with microbiome composition and diversity(Baseline to Day 1 of chemotherapy cycle 6. Each cycle is 3 weeks for regular schedule or 2 weeks for accelerated schedule, as per clinician decision.)
- Invasive disease-free survival (IDFS)(From enrollment in study and follow up for 10 years.)
- Distant recurrence-free survival(From enrollment in study and follow up for 10 years.)
- Overall survival (OS)(From enrollment in study and follow up for 10 years.)
- Rate of pathological response(Baseline to date of surgery in neoadjuvant patients.)