Breast Cancer Diet Intervention Study (BCDIS)

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

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.

Study Overview

• Status: Completed
• Conditions: Insulin Resistance; Estrogen Receptor-positive Breast Cancer; Early-stage Breast Cancer; Carbohydrate Engorgement; Proliferation
• Intervention / Treatment: Dietary supplement: PreOP

Detailed Description

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:

1. 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;
2. 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;
3. 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*
4. 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);
5. 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.
6. Estrogen Receptor positive tumors will be analyses separately.
7. Relapse free survival
8. 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:

1. Serum insulin characteristics (S-insulin, S- insulin c-peptide, S-IGF and S-IGFBP3) will be measured at various peri-surgical timepoints
2. Changes in metabolic profile* in the tumor and in serum samples
3. Patient Reported Outcome Measures (PROM) on well being
4. Relapse free survival

5. Breast Cancer Specific Survival

   • Metabolic profile assessed by High Resolution Magnetic Resonance Spectroscopy (HR-MRS) in the tumor and in serum samples.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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:

1. Non-operable patients (i.e" patients with T3-4 (>5 cm) disease or distant metastases at the time of operation).
2. All patients who refuse to participate.
3. All patients with DCIS, micro-invasive cancer < 2mm diameter or tumors with histologic poor-quality material.
4. Co-morbidity (Insulin dependent Diabetes Mellitus, Cushing syndrome, previous or concurrent cancers except CIN and non-melanomatous skin cancer.
5. Mental inability to participate.
6. Persons allergic to one of the compounds in any of the two diets.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Carbohydrate/intervention group; 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; Mixture of Carbohydrates; standard amount designed for enhanced recovery after surgery (ERAS) i.e. preoperative carbohydrate loading before long standing surgery to enhance recovery.
No Intervention: Control group; 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?

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

Collaborators and Investigators

• Sponsor: Helse Stavanger HF
• Investigators: Study Director: Svein Skeie, PhD, Helse Stavanger HF; Stavanger University Hospital

Publications and helpful links

General Publications

• Baak JP, van Diest PJ, Voorhorst FJ, van der Wall E, Beex LV, Vermorken JB, Janssen EA. Prospective multicenter validation of the independent prognostic value of the mitotic activity index in lymph node-negative breast cancer patients younger than 55 years. J Clin Oncol. 2005 Sep 1;23(25):5993-6001. doi: 10.1200/JCO.2005.05.511.
• Baak JP, Gudlaugsson E, Skaland I, Guo LH, Klos J, Lende TH, Soiland H, Janssen EA, Zur Hausen A. Proliferation is the strongest prognosticator in node-negative breast cancer: significance, error sources, alternatives and comparison with molecular prognostic markers. Breast Cancer Res Treat. 2009 May;115(2):241-54. doi: 10.1007/s10549-008-0126-y. Epub 2008 Jul 30.
• Lende TH, Austdal M, Bathen TF, Varhaugvik AE, Skaland I, Gudlaugsson E, Egeland NG, Lunde S, Akslen LA, Jonsdottir K, Janssen EAM, Soiland H, Baak JPA. Metabolic consequences of perioperative oral carbohydrates in breast cancer patients - an explorative study. BMC Cancer. 2019 Dec 4;19(1):1183. doi: 10.1186/s12885-019-6393-7.
• Lende TH, Austdal M, Varhaugvik AE, Skaland I, Gudlaugsson E, Kvaloy JT, Akslen LA, Soiland H, Janssen EAM, Baak JPA. Influence of pre-operative oral carbohydrate loading vs. standard fasting on tumor proliferation and clinical outcome in breast cancer patients horizontal line a randomized trial. BMC Cancer. 2019 Nov 8;19(1):1076. doi: 10.1186/s12885-019-6275-z.

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2009
• Primary Completion (Actual): July 7, 2017
• Study Completion (Actual): July 7, 2017

Study Registration Dates

• First Submitted: March 19, 2019
• First Submitted That Met QC Criteria: March 20, 2019
• First Posted (Actual): March 22, 2019

Study Record Updates

• Last Update Posted (Actual): May 13, 2019
• Last Update Submitted That Met QC Criteria: May 9, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Breast Cancer; Insulin resistance; Estrogen receptor positive; PROMs; Proliferation; RFS; NMRI; BCSS
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Hyperinsulinism; Breast Neoplasms; Insulin Resistance
• Other Study ID Numbers: 59

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: All data will be available to all researches involved in the study included the statistician allocated to the study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No