A 2-Week Ketogenic Diet in Combination With Letrozole to Modulate PI3K Signaling in ER+ Breast Cancer

A Pilot and Feasibility Neoadjuvant Study of a 2-Week Ketogenic Diet in Combination With Letrozole to Modulate PI3K Signaling in ER+ Breast Cancer

This is a neoadjuvant study to determine the feasibility and tolerability of 2 weeks of a very low carbohydrate ketogenic diet in combination with letrozole for patients with early stage operable ER+disease.

Study Overview

• Status: Completed
• Conditions: Estrogen Receptor-positive Breast Cancer
• Intervention / Treatment: Dietary supplement: 2-Week Ketogenic Diet; Drug: Letrozole

Detailed Description

Primary Objective:

• To evaluate the feasibility and tolerability of a 2 week ketogenic diet in combination with endocrine therapy prior to surgery for early stage ER+ breast cancer.

Secondary Objectives

• To determine whether endocrine therapy in combination with a dietary intervention to reduce insulin pathway signaling results in enhanced inhibition of cancer cell proliferation (measured byKi67)
• To determine the effectiveness of 2 weeks of a ketogenic diet to reduce measures of insulin/PI3Kpathway activation in breast tumors
• To measure changes in weight and body composition after 2 weeks of a ketogenic diet
• To measure changes in insulin resistance after 2 weeks of a ketogenic diet
• To measure the effectiveness of a ketogenic diet in combination with endocrine therapy to induce and maintain a ketogenic state.

Outline:

Participants will have baseline metabolic parameters measured and will begin a 2-week diet consisting of meal replacement shakes to induce a ketogenic state. Patients will also receive letrozole 2.5 mg daily. At the end of 2 weeks, metabolic parameters will again be measured and patients will proceed with surgical treatment of their breast cancer. A tumor biopsy from the surgical specimen will be obtained to measure cell proliferation compared with the pre-treatment diagnostic biopsy.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• All participants must provide written informed consent.

• Patients must have histologically confirmed primary invasive mammary carcinoma

  • The tumor must be estrogen receptor positive
  • The tumor must be HER2 negative (negative IHC or FISH)
  • The primary tumor size must be at least 2 mm in size.

• Patients must be post-menopausal defined by any of the following:

  • Subjects at least 55 years of age.
  • Subjects younger than 55 years of age and amenorrheic for at least 12 months or serum follicle-stimulating hormone (FSH) levels and estradiol levels in the post-menopausal range by local lab criteria
  • Subjects with history of bilateral oophorectomy or prior radiation castration with amenorrhea for at least 6 months.
• Patients must have clinical stage I, II, or III invasive mammary carcinoma planning to undergo surgical treatment with either segmental resection or total mastectomy.
• Patients must have BMI >= 30.
• A core biopsy from the time of diagnosis must be available.
• Mammogram or ultrasound required prior to screening

• Patients must have adequate organ function based on the following laboratory parameters:

  • Serum creatinine <= 1.5x ULN
  • SGOT, SGPT <= 4x ULN (unless known steatohepatitis)
  • Serum albumin >= 2.0 g/dL
  • Total serum bilirubin <= 1.5x ULN (or <= 3x ULN if known Gilbert's syndrome)

Exclusion Criteria:

Patients with locally advanced disease who are candidates for other preoperative (chemo)therapy at the time of initial evaluation. This includes patients with inflammatory breast cancer.

• Evidence of distant metastatic disease (stage IV).
• Serious medical illness that in the judgment of the treating physician places the patient at high risk of operative mortality.
• Serious medical illness that in the judgment of the treating physician would preclude the use of a ketogenic diet.
• Severe uncontrolled malabsorption condition or disease (e.g. grade II/III diarrhea, severe malnutrition, short gut syndrome).
• Diabetes mellitus requiring insulin therapy.
• Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
• Participation in any other neoadjuvant therapeutic clinical trial.
• Concurrent anti-cancer therapy other than endocrine therapy (e.g. chemotherapy, radiotherapy, immunotherapy, or any other biologic therapy).
• Concurrent treatment with an investigational agent.
• Use of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first day of dietary intervention.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 2-Week Ketogenic Diet; 2-Week Ketogenic Diet in Combination with Letrozole	Dietary supplement: 2-Week Ketogenic Diet; 2-Week Ketogenic Diet in Combination with Letrozole; Drug: Letrozole; 2.5 mg taken once daily by mouth
Active Comparator: Letrozole Control	Drug: Letrozole; 2.5 mg taken once daily by mouth

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patients who complete the dietary intervention	The number of patients who complete the dietary intervention, as well as the reasons for early discontinuation and any adverse events will be reported. The number of of cases where pre- and post-treatment samples could be obtained and successfully analyzed for Ki67 and insulin signaling will also be reported.	After 2 weeks of a ketogenic diet

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure enhanced inhibition of cancer cell proliferation	Measured by Ki67	After 2 weeks of a ketogenic diet
Reduction in measures of insulin/P13K pathway activation	Marks of insulin receptor/PI3K pathway activation in tumors	After 2 weeks of a ketogenic diet
Measure changes in body composition	Waist circumference will be measured	After 2 weeks of a ketogenic diet
Measure changes in body composition	Weight will be checked	After 2 weeks of a ketogenic diet
Measure changes in body composition	Height will be checked	After 2 weeks of a ketogenic diet
Measure changes in body composition	Body mass index will be measured	After 2 weeks of a ketogenic diet
Measure changes in insulin resistance	Fasting glucose/insulin to measure HOMA-IR	After 2 weeks of a ketogenic diet

Collaborators and Investigators

• Sponsor: Vanderbilt-Ingram Cancer Center
• Investigators: Principal Investigator: Brent Rexer, MD, PhD, Vanderbilt Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): July 8, 2019
• Primary Completion (Actual): March 7, 2024
• Study Completion (Actual): July 14, 2024

Study Registration Dates

• First Submitted: May 21, 2019
• First Submitted That Met QC Criteria: May 22, 2019
• First Posted (Actual): May 24, 2019

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 24, 2026
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Azoles; Diet, Food, and Nutrition; Physiological Phenomena; Nutritional Physiological Phenomena; Nitriles; Diet Therapy; Nutrition Therapy; Diet; Triazoles; Diet, Carbohydrate-Restricted; Letrozole; Diet, Ketogenic
• Other Study ID Numbers: VICC BRE 18108; NCI-2019-03071 (Registry Identifier: NCI, Clinical Trials Reporting Program)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No