Aromatase Inhibitor Host Factors Study

Patient-related Predictors of Estrogen Suppression in Postmenopausal Women Using Adjuvant Letrozole

The purpose of this study is to examine how key patient factors, including body size affect how well letrozole suppresses circulating estrogen levels.

This study has two components: (1) Part A - an observational phase to evaluate the impact of vitamin D and obesity on estrogen suppression in post-menopausal women already receiving letrozole treatment, and (2) Part B - an interventional phase for women with body mass index (BMI) > 25 kg/m2 to assess the effect of double AI dose on estrogen levels.

If BMI or other patient factors reduce the effectiveness of letrozole, modifications to treatment recommendations and studies to test higher dosing of letrozole may be needed to maximize the benefit of this treatment and minimize the risk of the breast cancer coming back.

Study Overview

• Status: Completed
• Conditions: Breast Neoplasms
• Intervention / Treatment: Drug: Letrozole

Detailed Description

The available evidence suggests that circulating estradiol levels play a critical role in determining effectiveness of aromatase inhibitor therapy, and that maximal suppression of aromatase activity and estrogen production is essential for optimal disease control. Host factors such as high 25-Hydroxy Vitamin D (25-OH D) levels and obesity, which might increase residual estrogen levels, could adversely impact outcome and lead to an increased risk of recurrence or death. The primary objective of Part A (which includes women regardless of BMI) is to directly evaluate the relationship between (i) 25-OH D levels and serum estrogen levels and (ii) BMI and serum estrogen levels in a cohort of postmenopausal women on standard dose letrozole therapy (2.5 mg/day). Part B (which includes only women with BMI > 25 kg/m2) will determine whether an increased dose of letrozole (5 mg/day), which had no dose limiting side effects in a Phase I study improves suppression of estrogen in overweight/obese women.

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada, M5G 1M9
      • Princess Margaret Hospital
    • Toronto, Ontario, Canada, M5S 1B1
      • Women's College Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Postmenopausal female patients
• histological confirmed diagnosis of estrogen receptor and/or progesterone receptor positive breast cancer (Stage I-III) who have completed local therapy
• Currently prescribed and taking letrozole 2.5 mg daily for a minimum of 3 months
• Willing to provide written informed consent to participate
• for the experimental arm: all of the above and body mass index (BMI) > 25 kg/m2

Exclusion Criteria:

• Known abnormal liver or renal function defined by:

  1. Serum Creatinine > 1.25 times institutional upper limit of normal (ULN) or Calculated Creatinine Clearance < 40 mL/min
  2. Serum Bilirubin, Aspartate transaminase (AST) or alanine transaminase (ALT) > 1.5 times ULN
• Presence of persistent local or known metastatic cancer

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Post-menopausal Women Using Adjuvant Letrozole; Part A Routine Care Letrozole; Part B Double Dose Letrozole in overweight/obese participants	Drug: Letrozole; Part A Monitor standard of care letrozole use for 28 days; measure blood levels of estrogens and vitamin D at start and end of period. Part B In overweight/obese participants who completed Part A, provide a double dose of letrozole and monitor use for 28 days; measure blood levels of estrogens and vitamin D at start and end of period.; Other Names: Femara

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A Correlation of Day 29 Estradiol With BMI	Determine if estradiol levels vary with BMI levels after 28 days of monitored adherence to standard dose letrozole, by calculating the Pearson correlation between estradiol and log-transformed BMI	Day 29
Part A Correlation of Day 29 Estrone With BMI	Determine if estrone levels vary with BMI levels after 28 days of monitored adherence to standard dose letrozole, by calculating the Pearson correlation between estrone and log-transformed BMI	Day 29
Part A Correlation of Day 29 Estradiol With Vitamin D	Determine if estradiol levels vary with Vitamin D levels levels after 28 days of monitored adherence to standard dose letrozole, by calculating the Pearson correlation between estradiol and log-transformed Vitamin D level	Day 29
Part A Correlation of Day 29 Estrone With Vitamin D	Determine if estrone levels vary with Vitamin D levels levels after 28 days of monitored adherence to standard dose letrozole, by calculating the Pearson correlation between estrone and log-transformed Vitamin D level	Day 29
Part B Change in Estradiol Level After Double Dose of Letrozole	In overweight/obese patients enrolled in part B, determine if blood levels of estradiol levels changed from before to after the double dose of letrozole	Day 29 to Day 58

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Letrozole		Day 29 and day 58
Endocrine Symptoms During Part A of Study	Functional Assessment of Cancer Therapy - Endocrine Sub-scale (FACT-ES) consists of 19 questions answered of a Likert scale. The sub-scale score ranges from 0 to 76 and the higher the score the better the quality of life	baseline, day 29 (end of part A)
Endocrine Symptoms During Part B of the Study	Functional Assessment of Cancer Therapy - Endocrine Sub-scale (FACT-ES) consists of 19 questions answered of a Likert scale. The sub-scale score ranges from 0 to 76 and the higher the score the better the quality of life	day 29 (end of part A) and day 58 (end of part B)

Other Outcome Measures

Outcome Measure	Time Frame
Musculoskeletal Symptoms	baseline (day 1), day 29 (end of part A) and day 58 (end of part B)

Collaborators and Investigators

• Sponsor: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
• Investigators: Principal Investigator: Srikala Sridhar, M.D., Princess Margaret Hospital, Canada

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2012
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: August 15, 2012
• First Submitted That Met QC Criteria: August 16, 2012
• First Posted (Estimate): August 21, 2012

Study Record Updates

• Last Update Posted (Actual): May 13, 2021
• Last Update Submitted That Met QC Criteria: May 12, 2021
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Aromatase Inhibitors
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: AI Host Factors

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The data supporting the related manuscript are kept in institutional file storage on an internal server at Lunenfeld-Tanenbaum Research Institute. There are de-identification concerns in small, regionally restricted, clinical datasets which prevent these data being openly available, but data will be made available at reasonable request from the corresponding author for up to and including 5 years from publication of the related manuscript.

For all data requests please contact:

Dr David Cescon, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Dave.Cescon@uhn.ca

• IPD Sharing Time Frame: Up to and including 5 years from publication of the related manuscript (Elliott, Mitchell J et al. "Association between BMI, vitamin D, and estrogen levels in postmenopausal women using adjuvant letrozole: a prospective study." NPJ breast cancer vol. 6 22. 12 Jun. 2020)
• IPD Sharing Access Criteria: Reasonable request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR