Clinical trial NCT03886389: Breast Cancer Diet Intervention Study
Official title: The Effects of Insulin and Insulin-related Characteristics, and Short-Term Low-glycemic and High-glycemic Carbohydrate Intervention on Breast Cancer Biomarkers and Survival
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Early-stage Breast Cancer
Carbohydrate Engorgement
Proliferation
Insulin Resistance
Estrogen Receptor-positive Breast Cancer
Keywords: Breast Cancer
Estrogen receptor positive
Proliferation
Insulin resistance
PROMs
NMRI
RFS
BCSS
Lead sponsor: Helse Stavanger HF
Sponsor class: OTHER_GOV
First posted: 2019-03-22
Enrollment: 80
Sex: FEMALE
Minimum age (years): 25
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Allocation: Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Mitotic Activity Index (MAI)
timeFrame: Trough completion of surgery of all included patients, an average of 1,5 years
Secondary outcomes:
measure: S-Insulin
timeFrame: 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)
measure: Well being after surgery
timeFrame: Day 1,2,3,4,5,6 and 7 after surgery
measure: High Resolution Magnetic Resonance Spectroscopy (HR-MRS) profiling of specific metabolites
timeFrame: 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)
measure: Relapse Free Survival
timeFrame: Until 8 years (97 months of follow up)
measure: Breast Cancer Specific Survival
timeFrame: 8 years follow-up (97 months of follow up)
measure: S-insulin c-peptide,
timeFrame: 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)
measure: S-IGF1
timeFrame: 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)
measure: S-IGFBP3
timeFrame: 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)
measure: PR
timeFrame: Trough completion of surgery of all included patients, an average of 1,5 years
Other outcomes:
Locations:
Study officials:
affiliation: Helse Stavanger HF; Stavanger University Hospital
name: Svein Skeie, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.