Breast Cancer Diet Intervention Study

Study Overview
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Brief Summary
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The investigators have already proven that Mitotic Activity Index (MAI)is the most robust measure of proliferation in breast cancer tissue. The purpose was to study whether 18 and 2-4 hours pre-operative per-oral carbohydrate loading (often given in gastrointestinal surgery i.e. enhanced recovery after surgery=ERAS) influences proliferation in the tumor, serum insulin characteristics, metabolic profile and survival.

Detailed Description
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It has been postulated that a Western-style diet, rich in carbohydrates (especially high glycemic carbohydrates) may have an effect on the incidence of breast cancer, and perhaps also prognosis. This may be mediated through the insulin-related pathways in breast cells which may show insulin-dependent proliferation, which may alter outcome. Aims: To study: The inter-patient variation in insulin and insulin-related characteristics in the blood taken just before the operation from breast cancer patients, on a usual pre-operative fasting schedule; The influence of the variation in insulin and insulin-related characteristics on proliferation and other cell biological features in the breast cancers of these patients; Whether 4 and 18-hours pre-operative hyperglycaemic glucose loading (to reduce postoperative insulin resistance) influences proliferation (Mitotic Activity Index (MAI) and other cell biological features in breast cancer* The influence of the short-term effect of a pre-operative low-glycaemic carbohydrate isocaloric diet on proliferation and other cell biological features of the primary breast cancer cells (Low-glycemic isocaloric diet intervention study); Epidemiological risk factors: The correlation between epidemiological risk factors, insulin and insulin-related characteristics, proliferation, cell biological features and other biomarkers in breast cancer patients. Estrogen Receptor positive tumors will be analyses separately. Relapse free survival Breast Cancer Specific Survival. The Short-term effect of carbohydrates will be assessed in a randomized intervention study, where 30 patients receive oral carbohydrates 18 and 4 hours before surgery and 30 patients receive fasting procedure/water. Primary Outcome 1. Proliferation in the tumor as measured by MAI. Secondary Outcomes: Serum insulin characteristics (S-insulin, S- insulin c-peptide, S-IGF and S-IGFBP3) will be measured at various peri-surgical timepoints Changes in metabolic profile* in the tumor and in serum samples Patient Reported Outcome Measures (PROM) on well being Relapse free survival Breast Cancer Specific Survival Metabolic profile assessed by High Resolution Magnetic Resonance Spectroscopy (HR-MRS) in the tumor and in serum samples.

Official Title
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The Effects of Insulin and Insulin-related Characteristics, and Short-Term Low-glycemic and High-glycemic Carbohydrate Intervention on Breast Cancer Biomarkers and Survival

Conditions
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Early-stage Breast Cancer, Carbohydrate Engorgement, Proliferation, Insulin Resistance, Estrogen Receptor-positive Breast Cancer

Intervention / Treatment
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* Dietary Supplement: PreOP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All consecutive operable patients in 2009-2010, with a clinical and/or radiologic and/or cytologic diagnosis of primary breast cancer, unless the exclusion criteria apply. Exclusion Criteria: Non-operable patients (i.e patients with T3-4 (>5 cm) disease or distant metastases at the time of operation). All patients who refuse to participate. All patients with DCIS, micro-invasive cancer < 2mm diameter or tumors with histologic poor-quality material. Co-morbidity (Insulin dependent Diabetes Mellitus, Cushing syndrome, previous or concurrent cancers except CIN and non-melanomatous skin cancer. Mental inability to participate. Persons allergic to one of the compounds in any of the two diets.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Allocation: Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carbohydrate/intervention group<br>Breast cancer patients receive 2 x preoperative carbohydrate loading [PreOP(TM)] before surgery; the 1st dose 18 hours before and 2nd dose 2-4 hours before surgery. | Dietary Supplement: PreOP<br>* Mixture of Carbohydrates; standard amount designed for enhanced recovery after surgery (ERAS) i.e. preoperative carbohydrate loading before long standing surgery to enhance recovery.<br>|
| No Intervention: Control group<br>Breast cancer patients receive standard prep fasting procedure with nil food per os 8-10 hours before surgery, drinking tap water until 2 hours before surgery. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mitotic Activity Index (MAI) | Proliferation in invasive front in tumor | Trough completion of surgery of all included patients, an average of 1,5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| S-Insulin | Secretion of insulin into serum; unit, mIE/L (milli international units pr liter) | Analysed in serum samples at 5 time points; At inclusion (day 0), admission (day 10), preoperatively (day 11), postoperatively (day12) and at post operative visit (day 30) | 
| Well being after surgery | Patient Reported Outcome Measures (Questionaire) | Day 1,2,3,4,5,6 and 7 after surgery | 
| High Resolution Magnetic Resonance Spectroscopy (HR-MRS) profiling of specific metabolites | Metabolic profiling in the primary tumor and in the serum samples; measure content of lactate, glycine, choline, fatty acids and lipoproteins | Immediately after surgery: tumor is fresh frozen. High Resolution Magnetic Resonance Spectroscopy (HR-MRS) will be done in the fresh frozen tumor and deep frozen serum samples (=as for insulin characteristics) | 
| Relapse Free Survival | Time from surgery to a relapse (Loco-regional, contralateral and systemic) is experienced | Until 8 years (97 months of follow up) | 
| Breast Cancer Specific Survival | Time from surgery to dead of disease or all other causes of death. | 8 years follow-up (97 months of follow up) | 
| S-insulin c-peptide, | Measure of total insulin secreted; unit, nM (nano molar) | Analysed in serum samples at 5 time points; At inclusion (day 0), admission (day 10), preoperatively (day 11), postoperatively (day12) and at post operative visit (day 30) | 
| S-IGF1 | Measure of Insulin growth factor type 1; unit, nM (nano molar) | Analysed in serum samples at 5 time points; At inclusion (day 0), admission (day 10), preoperatively (day 11), postoperatively (day12) and at post operative visit (day 30) | 
| S-IGFBP3 | Measure of Insulin growth factor binding protein 3; unit mg/L (milligram per liter) | Analysed in serum samples at 5 time points; At inclusion (day 0), admission (day 10), preoperatively (day 11), postoperatively (day12) and at post operative visit (day 30) | 
| PR | Expression of Progesteron Receptor in the primary tumor | Trough completion of surgery of all included patients, an average of 1,5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Estrogen receptor positive, Proliferation, Insulin resistance, PROMs, NMRI, RFS, BCSS